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    CNKSR2 connector enhancer of kinase suppressor of Ras 2 [ Homo sapiens (human) ]

    Gene ID: 22866, updated on 28-Oct-2024

    Summary

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    Official Symbol
    CNKSR2provided by HGNC
    Official Full Name
    connector enhancer of kinase suppressor of Ras 2provided by HGNC
    Primary source
    HGNC:HGNC:19701
    See related
    Ensembl:ENSG00000149970 MIM:300724; AllianceGenome:HGNC:19701
    Gene type
    protein coding
    RefSeq status
    REVIEWED
    Organism
    Homo sapiens
    Lineage
    Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
    Also known as
    CNK2; KSR2; MAGUIN; MRXSHG
    Summary
    This gene encodes a multidomain protein that functions as a scaffold protein to mediate the mitogen-activated protein kinase pathways downstream from Ras. This gene product is induced by vitamin D and inhibits apoptosis in certain cancer cells. It may also play a role in ternary complex assembly of synaptic proteins at the postsynaptic membrane and coupling of signal transduction to membrane/cytoskeletal remodeling. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2009]
    Expression
    Biased expression in brain (RPKM 9.7), adrenal (RPKM 1.3) and 2 other tissues See more
    Orthologs
    mouse all
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    Genomic context

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    See CNKSR2 in Genome Data Viewer
    Location:
    Xp22.12
    Exon count:
    23
    Annotation release Status Assembly Chr Location
    RS_2024_08 current GRCh38.p14 (GCF_000001405.40) X NC_000023.11 (21374418..21654689)
    RS_2024_08 current T2T-CHM13v2.0 (GCF_009914755.1) X NC_060947.1 (20957756..21238011)
    RS_2024_09 previous assembly GRCh37.p13 (GCF_000001405.25) X NC_000023.10 (21392536..21672807)

    Chromosome X - NC_000023.11Genomic Context describing neighboring genes Neighboring gene uncharacterized LOC124905258 Neighboring gene OCT4-NANOG hESC enhancer GRCh37_chrX:20991102-20991662 Neighboring gene CDK7 strongly-dependent group 2 enhancer GRCh37_chrX:21007714-21008913 Neighboring gene OCT4-NANOG hESC enhancer GRCh37_chrX:21064982-21065616 Neighboring gene NANOG hESC enhancer GRCh37_chrX:21176863-21177381 Neighboring gene RNA, U6 small nuclear 133, pseudogene Neighboring gene uncharacterized LOC105373146 Neighboring gene H3K4me1 hESC enhancer GRCh37_chrX:21357913-21358412 Neighboring gene H3K4me1 hESC enhancer GRCh37_chrX:21391460-21391960 Neighboring gene H3K4me1 hESC enhancer GRCh37_chrX:21391961-21392461 Neighboring gene retinoic acid receptor responder 2 pseudogene 3 Neighboring gene BRD4-independent group 4 enhancer GRCh37_chrX:21704726-21705925 Neighboring gene kelch like family member 34 Neighboring gene small muscle protein X-linked

    Genomic regions, transcripts, and products

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    Go to nucleotide: Graphics FASTA GenBank

    Expression

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    • Project title: HPA RNA-seq normal tissues HPA RNA-seq normal tissues
    • Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
    • BioProject: PRJEB4337
    • Publication: PMID 24309898
    • Analysis date: Wed Apr 4 07:08:55 2018

    Bibliography

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    Related articles in PubMed

    1. hKSR-2, a vitamin D-regulated gene, inhibits apoptosis in arabinocytosine-treated HL60 leukemia cells. Wang X, et al. Mol Cancer Ther, 2008 Sep. PMID 18790760, Free PMC Article
    2. Functions of CNKSR2 and Its Association with Neurodevelopmental Disorders. Ito H, et al. Cells, 2022 Jan 17. PMID 35053419, Free PMC Article
    3. Absent CNKSR2 causes seizures and intellectual, attention, and language deficits. Vaags AK, et al. Ann Neurol, 2014 Nov. PMID 25223753
    4. CNKSR2 deletions: a novel cause of X-linked intellectual disability and seizures. Aypar U, et al. Am J Med Genet A, 2015 Jul. PMID 25754917
    5. Psychomotor development and attention problems caused by a splicing variant of CNKSR2. Zhang Y, et al. BMC Med Genomics, 2020 Dec 9. PMID 33298018, Free PMC Article

    See all (42) citations in PubMed

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?
    1. Functions of CNKSR2 and Its Association with Neurodevelopmental Disorders.
      Title: Functions of CNKSR2 and Its Association with Neurodevelopmental Disorders.
    2. Finding underlying genetic mechanisms of two patients with autism spectrum disorder carrying familial apparently balanced chromosomal translocations.
      Title: Finding underlying genetic mechanisms of two patients with autism spectrum disorder carrying familial apparently balanced chromosomal translocations.
    3. Psychomotor development and attention problems caused by a splicing variant of CNKSR2.
      Title: Psychomotor development and attention problems caused by a splicing variant of CNKSR2.
    4. Expanding the clinical and EEG spectrum of CNKSR2-related encephalopathy with status epilepticus during slow sleep (ESES).
      Title: Expanding the clinical and EEG spectrum of CNKSR2-related encephalopathy with status epilepticus during slow sleep (ESES).
    5. This study enhances our knowledge of the CNKSR2 gene mutation spectrum and provides further information about the phenotypic characteristics of X-linked syndromic intellectual disability.
      Title: Exons deletion of CNKSR2 gene identified in X-linked syndromic intellectual disability.
    6. High CNKSR2 expression is associated with breast cancer progression.
      Title: Regulation of CNKSR2 protein stability by the HECT E3 ubiquitin ligase Smurf2, and its role in breast cancer progression.
    7. CNKSR2 deletions: a novel cause of X-linked intellectual disability and seizures.
      Title: CNKSR2 deletions: a novel cause of X-linked intellectual disability and seizures.
    8. This study describes the phenotype of CNKSR2 deficiency and its involvement in systems underlying common neurological
      Title: Absent CNKSR2 causes seizures and intellectual, attention, and language deficits.
    9. CNK and HYP form a discrete dimer by their SAM domains to mediate RAF kinase signaling.
      Title: CNK and HYP form a discrete dimer by their SAM domains to mediate RAF kinase signaling.
    10. CNK2 through interaction with Raf and Rlf may function as a regulator of Ras signaling.
      Title: Human homologue of Drosophila CNK interacts with Ras effector proteins Raf and Rlf.
    Submit: New GeneRIF Correction

    Phenotypes

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    Find tests for this gene in the NIH Genetic Testing Registry (GTR)

    Review eQTL and phenotype association data in this region using PheGenI

    Associated conditions

    Description Tests
    Intellectual disability, X-linked, syndromic, Houge type
    MedGen: C4538788 OMIM: 301008 GeneReviews: Not available
    		Compare labs

    Copy number response

    Description
    Copy number response
    Triplosensitivity

    No evidence available (Last evaluated 2021-01-12)

    ClinGen Genome Curation Page
    Haploinsufficency

    Sufficient evidence for dosage pathogenicity (Last evaluated 2021-01-12)

    ClinGen Genome Curation PagePubMed

    EBI GWAS Catalog

    Description
    Biological insights from 108 schizophrenia-associated genetic loci.
    EBI GWAS Catalog

    Variation

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    See variants in ClinVar

    See studies and variants in dbVar

    See Variation Viewer (GRCh37.p13)

    See Variation Viewer (GRCh38)

    Genotypes

    Interactions

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    Products Interactant Other Gene Complex Source Pubs Description

    General gene information

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    Markers

    Homology

    Clone Names

    • KIAA0902

    Gene Ontology Provided by GOA

    Function Evidence Code Pubs
    enables identical protein binding IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables protein binding IPI
    Inferred from Physical Interaction
    more info
    		 PubMed 
    enables protein kinase binding IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    Process Evidence Code Pubs
    acts_upstream_of_or_within intracellular signal transduction IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in postsynaptic specialization organization IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in regulation of signal transduction IEA
    Inferred from Electronic Annotation
    more info
    		  
    Component Evidence Code Pubs
    located_in cytoplasm IEA
    Inferred from Electronic Annotation
    more info
    		  
    located_in extracellular exosome HDA PubMed 
    located_in extrinsic component of postsynaptic density membrane IEA
    Inferred from Electronic Annotation
    more info
    		  
    located_in glutamatergic synapse IEA
    Inferred from Electronic Annotation
    more info
    		  
    located_in neuronal cell body IEA
    Inferred from Electronic Annotation
    more info
    		  
    located_in plasma membrane IDA
    Inferred from Direct Assay
    more info
    		 PubMed 

    General protein information

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    Preferred Names
    connector enhancer of kinase suppressor of ras 2
    Names
    CNK homolog protein 2
    connector enhancer of KSR2
    membrane-associated guanylate kinase-interacting protein

    NCBI Reference Sequences (RefSeq)

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    RefSeqs maintained independently of Annotated Genomes

    These reference sequences exist independently of genome builds. Explain

    These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

    Genomic

    1. NG_016266.1 RefSeqGene

      Range
      5001..285272
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. NM_001168647.3 → NP_001162118.1  connector enhancer of kinase suppressor of ras 2 isoform 2

      See identical proteins and their annotated locations for NP_001162118.1

      Status: REVIEWED

      Source sequence(s)
      AL772392, AL807781, BC143839
      Consensus CDS
      CCDS55388.1
      UniProtKB/TrEMBL
      A0A2R8YED7
      Related
      ENSP00000397906.2, ENST00000425654.7
      Conserved Domains (5) summary
      cd09511
      Location:8 → 76
      SAM_CNK1,2,3-suppressor; SAM domain of CNK1,2,3-suppressor subfamily
      cd00992
      Location:222 → 294
      PDZ_signaling; PDZ domain found in a variety of Eumetazoan signaling molecules, often in tandem arrangements. May be responsible for specific protein-protein interactions, as most PDZ domains bind C-terminal polypeptides, and binding to internal (non-C-terminal) ...
      cd01260
      Location:529 → 642
      PH_CNK_mammalian-like; Connector enhancer of KSR (Kinase suppressor of ras) (CNK) pleckstrin homology (PH) domain
      pfam06663
      Location:339 → 484
      DUF1170; Protein of unknown function (DUF1170)
      pfam10534
      Location:84 → 176
      CRIC_ras_sig; Connector enhancer of kinase suppressor of ras

    2. NM_001168648.3 → NP_001162119.1  connector enhancer of kinase suppressor of ras 2 isoform 3

      See identical proteins and their annotated locations for NP_001162119.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (3, also known as CNK2B and MAGUIN-2) differs in the 3' UTR and 3' coding region, compared to variant 1. It encodes isoform 3 which has a shorter and distinct C-terminus, compared to isoform 1.
      Source sequence(s)
      AF418270, AK056549, AL772392, BM692904, DA067208, F09543, T65396, Z40257
      Consensus CDS
      CCDS55387.1
      UniProtKB/TrEMBL
      A0A2R8YGJ7
      Related
      ENSP00000496709.1, ENST00000642359.1
      Conserved Domains (5) summary
      cd09511
      Location:8 → 76
      SAM_CNK1,2,3-suppressor; SAM domain of CNK1,2,3-suppressor subfamily
      cd00992
      Location:222 → 294
      PDZ_signaling; PDZ domain found in a variety of Eumetazoan signaling molecules, often in tandem arrangements. May be responsible for specific protein-protein interactions, as most PDZ domains bind C-terminal polypeptides, and binding to internal (non-C-terminal) ...
      cd01260
      Location:559 → 672
      PH_CNK_mammalian-like; Connector enhancer of KSR (Kinase suppressor of ras) (CNK) pleckstrin homology (PH) domain
      pfam06663
      Location:339 → 514
      DUF1170; Protein of unknown function (DUF1170)
      pfam10534
      Location:84 → 176
      CRIC_ras_sig; Connector enhancer of kinase suppressor of ras

    3. NM_001168649.3 → NP_001162120.1  connector enhancer of kinase suppressor of ras 2 isoform 4

      See identical proteins and their annotated locations for NP_001162120.1

      Status: REVIEWED

      Source sequence(s)
      AK056549, AK294728, AL772392, AL807781, F09543, T65396, Z40257
      Consensus CDS
      CCDS55389.1
      UniProtKB/TrEMBL
      A0A2R8YGJ7
      Related
      ENSP00000444633.1, ENST00000543067.6
      Conserved Domains (5) summary
      cd09511
      Location:8 → 76
      SAM_CNK1,2,3-suppressor; SAM domain of CNK1,2,3-suppressor subfamily
      cd00992
      Location:222 → 270
      PDZ_signaling; PDZ domain found in a variety of Eumetazoan signaling molecules, often in tandem arrangements. May be responsible for specific protein-protein interactions, as most PDZ domains bind C-terminal polypeptides, and binding to internal (non-C-terminal) ...
      cd01260
      Location:510 → 623
      PH_CNK_mammalian-like; Connector enhancer of KSR (Kinase suppressor of ras) (CNK) pleckstrin homology (PH) domain
      pfam06663
      Location:290 → 465
      DUF1170; Protein of unknown function (DUF1170)
      pfam10534
      Location:84 → 176
      CRIC_ras_sig; Connector enhancer of kinase suppressor of ras

    4. NM_001330770.2 → NP_001317699.1  connector enhancer of kinase suppressor of ras 2 isoform 5

      Status: REVIEWED

      Source sequence(s)
      AL772392, AL807781, AL928874
      Consensus CDS
      CCDS87729.1
      UniProtKB/TrEMBL
      A0A2R8Y7A1, A0A2R8YED7
      Related
      ENSP00000495954.1, ENST00000644585.1
      Conserved Domains (5) summary
      cd09511
      Location:8 → 76
      SAM_CNK1,2,3-suppressor; SAM domain of CNK1,2,3-suppressor subfamily
      cd00992
      Location:222 → 270
      PDZ_signaling; PDZ domain found in a variety of Eumetazoan signaling molecules, often in tandem arrangements. May be responsible for specific protein-protein interactions, as most PDZ domains bind C-terminal polypeptides, and binding to internal (non-C-terminal) ...
      cd01260
      Location:510 → 623
      PH_CNK_mammalian-like; Connector enhancer of KSR (Kinase suppressor of ras) (CNK) pleckstrin homology (PH) domain
      pfam06663
      Location:290 → 465
      DUF1170; Protein of unknown function (DUF1170)
      pfam10534
      Location:84 → 176
      CRIC_ras_sig; Connector enhancer of kinase suppressor of ras

    5. NM_001330771.2 → NP_001317700.1  connector enhancer of kinase suppressor of ras 2 isoform 6

      Status: REVIEWED

      Source sequence(s)
      AL772392, AL807781, AL928874
      Consensus CDS
      CCDS87730.1
      UniProtKB/TrEMBL
      A0A2R8Y5S6, A0A2R8Y622
      Related
      ENSP00000494906.1, ENST00000645791.1
      Conserved Domains (5) summary
      cd09511
      Location:8 → 76
      SAM_CNK1,2,3-suppressor; SAM domain of CNK1,2,3-suppressor subfamily
      cd00992
      Location:222 → 270
      PDZ_signaling; PDZ domain found in a variety of Eumetazoan signaling molecules, often in tandem arrangements. May be responsible for specific protein-protein interactions, as most PDZ domains bind C-terminal polypeptides, and binding to internal (non-C-terminal) ...
      cd01260
      Location:480 → 593
      PH_CNK_mammalian-like; Connector enhancer of KSR (Kinase suppressor of ras) (CNK) pleckstrin homology (PH) domain
      pfam06663
      Location:290 → 408
      DUF1170; Protein of unknown function (DUF1170)
      pfam10534
      Location:84 → 176
      CRIC_ras_sig; Connector enhancer of kinase suppressor of ras

    6. NM_001330772.2 → NP_001317701.1  connector enhancer of kinase suppressor of ras 2 isoform 7

      Status: REVIEWED

      Source sequence(s)
      AL772392, AL807781, AL928874
      Consensus CDS
      CCDS87731.1
      UniProtKB/TrEMBL
      A0A2R8Y700, A0A2R8YED7
      Related
      ENSP00000495695.1, ENST00000645245.1
      Conserved Domains (5) summary
      cd09511
      Location:8 → 76
      SAM_CNK1,2,3-suppressor; SAM domain of CNK1,2,3-suppressor subfamily
      cd00992
      Location:222 → 270
      PDZ_signaling; PDZ domain found in a variety of Eumetazoan signaling molecules, often in tandem arrangements. May be responsible for specific protein-protein interactions, as most PDZ domains bind C-terminal polypeptides, and binding to internal (non-C-terminal) ...
      cd01260
      Location:480 → 593
      PH_CNK_mammalian-like; Connector enhancer of KSR (Kinase suppressor of ras) (CNK) pleckstrin homology (PH) domain
      pfam06663
      Location:290 → 435
      DUF1170; Protein of unknown function (DUF1170)
      pfam10534
      Location:84 → 176
      CRIC_ras_sig; Connector enhancer of kinase suppressor of ras

    7. NM_001330773.2 → NP_001317702.1  connector enhancer of kinase suppressor of ras 2 isoform 8

      Status: REVIEWED

      Source sequence(s)
      AL772392, AL807781, AL928874
      Consensus CDS
      CCDS87728.1
      UniProtKB/TrEMBL
      A0A2R8Y5S6, A0A2U3TZH5
      Related
      ENSP00000279451.5, ENST00000279451.9
      Conserved Domains (5) summary
      cd09511
      Location:8 → 76
      SAM_CNK1,2,3-suppressor; SAM domain of CNK1,2,3-suppressor subfamily
      cd00992
      Location:222 → 294
      PDZ_signaling; PDZ domain found in a variety of Eumetazoan signaling molecules, often in tandem arrangements. May be responsible for specific protein-protein interactions, as most PDZ domains bind C-terminal polypeptides, and binding to internal (non-C-terminal) ...
      cd01260
      Location:529 → 642
      PH_CNK_mammalian-like; Connector enhancer of KSR (Kinase suppressor of ras) (CNK) pleckstrin homology (PH) domain
      pfam06663
      Location:339 → 457
      DUF1170; Protein of unknown function (DUF1170)
      pfam10534
      Location:84 → 176
      CRIC_ras_sig; Connector enhancer of kinase suppressor of ras

    8. NM_014927.5 → NP_055742.2  connector enhancer of kinase suppressor of ras 2 isoform 1

      See identical proteins and their annotated locations for NP_055742.2

      Status: REVIEWED

      Description
      Transcript Variant: This variant (1, also known as CNK2A and MAGUIN-1) represents the longest transcript and encodes the longest isoform (1).
      Source sequence(s)
      AL772392, AL807781, BC136289
      Consensus CDS
      CCDS14198.1
      UniProtKB/Swiss-Prot
      B4DGR4, B7ZLJ1, B9EG83, E7ESA4, O94976, Q5JPK4, Q5JPN0, Q8WXI1, Q8WXI2
      UniProtKB/TrEMBL
      A0A2R8YED7
      Related
      ENSP00000368824.3, ENST00000379510.5
      Conserved Domains (5) summary
      cd09511
      Location:8 → 76
      SAM_CNK1,2,3-suppressor; SAM domain of CNK1,2,3-suppressor subfamily
      cd00992
      Location:222 → 294
      PDZ_signaling; PDZ domain found in a variety of Eumetazoan signaling molecules, often in tandem arrangements. May be responsible for specific protein-protein interactions, as most PDZ domains bind C-terminal polypeptides, and binding to internal (non-C-terminal) ...
      cd01260
      Location:559 → 672
      PH_CNK_mammalian-like; Connector enhancer of KSR (Kinase suppressor of ras) (CNK) pleckstrin homology (PH) domain
      pfam06663
      Location:339 → 514
      DUF1170; Protein of unknown function (DUF1170)
      pfam10534
      Location:84 → 176
      CRIC_ras_sig; Connector enhancer of kinase suppressor of ras

    RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2024_08

    The following sections contain reference sequences that belong to a specific genome build. Explain

    Reference GRCh38.p14 Primary Assembly

    Genomic

    1. NC_000023.11 Reference GRCh38.p14 Primary Assembly

      Range
      21374418..21654689
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_011545471.4 → XP_011543773.1  connector enhancer of kinase suppressor of ras 2 isoform X1

      UniProtKB/TrEMBL
      A0A2R8Y5S6
      Conserved Domains (8) summary
      cd09511
      Location:8 → 76
      SAM_CNK1,2,3-suppressor; SAM domain of CNK1,2,3-suppressor subfamily
      smart00454
      Location:8 → 73
      SAM; Sterile alpha motif
      cd00992
      Location:222 → 294
      PDZ_signaling; PDZ domain found in a variety of Eumetazoan signaling molecules, often in tandem arrangements. May be responsible for specific protein-protein interactions, as most PDZ domains bind C-terminal polypeptides, and binding to internal (non-C-terminal) ...
      cd01260
      Location:529 → 642
      PH_CNK_mammalian-like; Connector enhancer of KSR (Kinase suppressor of ras) (CNK) pleckstrin homology (PH) domain
      pfam00169
      Location:543 → 639
      PH; PH domain
      pfam06663
      Location:341 → 531
      DUF1170; Protein of unknown function (DUF1170)
      pfam10534
      Location:84 → 176
      CRIC_ras_sig; Connector enhancer of kinase suppressor of ras
      pfam15499
      Location:139 → 218
      Peptidase_C98; Ubiquitin-specific peptidase-like, SUMO isopeptidase

    2. XM_011545472.4 → XP_011543774.1  connector enhancer of kinase suppressor of ras 2 isoform X2

      See identical proteins and their annotated locations for XP_011543774.1

      UniProtKB/TrEMBL
      A0A2R8YGJ7
      Conserved Domains (8) summary
      cd09511
      Location:8 → 76
      SAM_CNK1,2,3-suppressor; SAM domain of CNK1,2,3-suppressor subfamily
      smart00454
      Location:8 → 73
      SAM; Sterile alpha motif
      cd00992
      Location:222 → 270
      PDZ_signaling; PDZ domain found in a variety of Eumetazoan signaling molecules, often in tandem arrangements. May be responsible for specific protein-protein interactions, as most PDZ domains bind C-terminal polypeptides, and binding to internal (non-C-terminal) ...
      cd01260
      Location:510 → 623
      PH_CNK_mammalian-like; Connector enhancer of KSR (Kinase suppressor of ras) (CNK) pleckstrin homology (PH) domain
      pfam00169
      Location:524 → 620
      PH; PH domain
      pfam06663
      Location:292 → 512
      DUF1170; Protein of unknown function (DUF1170)
      pfam10534
      Location:84 → 176
      CRIC_ras_sig; Connector enhancer of kinase suppressor of ras
      pfam15499
      Location:139 → 218
      Peptidase_C98; Ubiquitin-specific peptidase-like, SUMO isopeptidase

    3. XM_017029358.3 → XP_016884847.1  connector enhancer of kinase suppressor of ras 2 isoform X3

      UniProtKB/TrEMBL
      A0A2R8Y5S6

    Alternate T2T-CHM13v2.0

    Genomic

    1. NC_060947.1 Alternate T2T-CHM13v2.0

      Range
      20957756..21238011
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)
    Nucleotide Protein
    Heading Accession and Version
    Protein Accession Links
    GenPept Link UniProtKB Link
    Q8WXI2.1 GenPept UniProtKB/Swiss-Prot:Q8WXI2

    Gene LinkOut

    The following LinkOut resources are supplied by external providers. These providers are responsible for maintaining the links.

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