VCV000984881.9 - ClinVar

NM_177559.3(CSNK2A1):c.934C>T (p.Arg312Trp)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(6)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_177559.3(CSNK2A1):c.934C>T (p.Arg312Trp)

Variation ID: 984881 Accession: VCV000984881.9

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 20p13 20: 487466 (GRCh38) [ NCBI UCSC ] 20: 468110 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Nov 21, 2020	Jul 23, 2024	Feb 15, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_177559.3:c.934C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_808227.1:p.Arg312Trp	missense
NM_001362770.2:c.934C>T	NP_001349699.1:p.Arg312Trp	missense
NM_001362771.2:c.934C>T	NP_001349700.1:p.Arg312Trp	missense
NM_001895.4:c.934C>T	NP_001886.1:p.Arg312Trp	missense
NM_177560.2:c.526C>T
NM_177560.3:c.526C>T	NP_808228.1:p.Arg176Trp	missense
NC_000020.11:g.487466G>A
NC_000020.10:g.468110G>A
NG_011970.2:g.61373C>T

... more HGVS ... less HGVS

Protein change

R176W, R312W

Other names

Canonical SPDI

NC_000020.11:487465:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

dbSNP: rs2018124491 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
CSNK2A1		Little evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	188	264

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Okur-Chung neurodevelopmental syndrome	Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Feb 8, 2023	RCV001265462.3
Inborn genetic diseases	Likely pathogenic (1)	criteria provided, single submitter	Jan 14, 2019	RCV001266556.2
not provided	Pathogenic (1)	criteria provided, single submitter	Feb 15, 2024	RCV001572170.4
Developmental disorder	Pathogenic (1)	criteria provided, single submitter	May 23, 2022	RCV003127743.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Jan 14, 2019)	criteria provided, single submitter (Ambry exome assertion method (8-5-2015)) Method: clinical testing	Inborn genetic diseases Affected status: yes Allele origin: germline	Ambry Genetics Accession: SCV001444732.2 First in ClinVar: Nov 21, 2020 Last updated: Jan 07, 2023	Publications: PubMed (5) PubMed: 28135719‚ 11574463‚ 29383814‚ 27048600‚ 24395637 Number of individuals with the variant: 1 Clinical Features: Failure to thrive (present) , Muscular hypotonia (present) , Global developmental delay (present) , Obstructive sleep apnea syndrome (present) , Relative macrocephaly (present) , Otitis … (more) Failure to thrive (present) , Muscular hypotonia (present) , Global developmental delay (present) , Obstructive sleep apnea syndrome (present) , Relative macrocephaly (present) , Otitis media (present) , Dysphagia (present) , Short neck (present) , Frontal bossing (present) , Pectus excavatum (present) , Short stature (present) , Epicanthus (present) , Stereotypy (present) , Hearing impairment (present) (less) Sex: male Ethnicity/Population group: Caucasian
Pathogenic (May 23, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental disorder Affected status: yes Allele origin: de novo	Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine Accession: SCV003804095.1 First in ClinVar: Feb 18, 2023 Last updated: Feb 18, 2023	Sex: male
Likely pathogenic (Feb 08, 2023)	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020) Method: clinical testing	Okur-Chung neurodevelopmental syndrome Affected status: unknown Allele origin: unknown	Illumina Laboratory Services, Illumina Accession: SCV004014720.1 First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023	Publications: PubMed (3) PubMed: 33944995‚ 29240241‚ 29383814 Comment: The CSNK2A1 c.934C>T (p.Arg312Trp) missense variant results in the substitution of arginine at amino acid position 312 with tryptophan. This variant has been reported in … (more) The CSNK2A1 c.934C>T (p.Arg312Trp) missense variant results in the substitution of arginine at amino acid position 312 with tryptophan. This variant has been reported in a heterozygous state with de novo occurrence in an individual with Okur-Chung neurodevelopmental syndrome in the literature (PMID: 29383814). Another variant at the same amino acid position, c.935G>A p.(Arg312Gln), has also been reported in a heterozygous state with de novo occurrence in an affected individual (PMID: 29240241). This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Functional assessment of the c.934C>T variant performed in mammalian cells shows reduced kinase activity and reduced protein expression compared to wildtype (PMID: 33944995). Based on the available evidence, the c.934C>T (p.Arg312Trp) variant is classified as likely pathogenic for Okur-Chung neurodevelopmental syndrome. (less)
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Okur-Chung neurodevelopmental syndrome (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV005073917.1 First in ClinVar: Jul 15, 2024 Last updated: Jul 15, 2024	Comment: The observed missense c.934C>T (p.Arg312Trp) variant in CSNK2A1 gene has been reported in multiple individuals affected CSNK2A1-related disorders (Owen et al., 2018; Deciphering Developmental Disorders … (more) The observed missense c.934C>T (p.Arg312Trp) variant in CSNK2A1 gene has been reported in multiple individuals affected CSNK2A1-related disorders (Owen et al., 2018; Deciphering Developmental Disorders Study, 2017; Chiu et al., 2018). The p.Arg312Trp variant is absent in the gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic (multiple submissions) / Likely Pathogenic. The amino acid change p.Arg312Trp in CSNK2A1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates.The amino acid Arg at position 312 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. Additional functional studies will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as Likely Pathogenic. (less)
Pathogenic (Feb 15, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001796763.2 First in ClinVar: Aug 21, 2021 Last updated: Jul 23, 2024	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more) Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29383814, 28135719, 24395637, 11574463, 33944995, 31785789, 27048600, 29240241) (less)
Pathogenic (Sep 17, 2018)	no assertion criteria provided Method: provider interpretation	Okur-Chung neurodevelopmental syndrome Affected status: yes Allele origin: de novo	GenomeConnect - Simons Searchlight Accession: SCV001443597.1 First in ClinVar: Nov 21, 2020 Last updated: Nov 21, 2020	Comment: Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-09-17 and interpreted as Pathogenic. Variant was initially … (more) Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-09-17 and interpreted as Pathogenic. Variant was initially reported on 2018-06-11 by GTR ID of laboratory name 26957. The reporting laboratory might also submit to ClinVar. (less) Clinical Features: Autistic behavior (present) , Echogenic intracardiac focus (present) , Caesarian section (present) , Neonatal hypotonia (present) , Feeding difficulties in infancy (present) , Strabismus (present) … (more) Autistic behavior (present) , Echogenic intracardiac focus (present) , Caesarian section (present) , Neonatal hypotonia (present) , Feeding difficulties in infancy (present) , Strabismus (present) , Generalized hypotonia (present) , Microcephaly (present) , Cerebral palsy (present) , Seizures (present) , Absence seizures (present) , Constipation (present) , Otitis media (present) , Hypothyroidism (present) , Abnormality of the skin (present) , Eczema (present) (less) Age: 10-19 years Sex: female Testing laboratory: GeneDx Date variant was reported to submitter: 2018-06-11 Testing laboratory interpretation: Pathogenic

Comment:

The CSNK2A1 c.934C>T (p.Arg312Trp) missense variant results in the substitution of arginine at amino acid position 312 with tryptophan. This variant has been reported in a heterozygous state with de novo occurrence in an individual with Okur-Chung neurodevelopmental syndrome in the literature (PMID: 29383814). Another variant at the same amino acid position, c.935G>A p.(Arg312Gln), has also been reported in a heterozygous state with de novo occurrence in an affected individual (PMID: 29240241). This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Functional assessment of the c.934C>T variant performed in mammalian cells shows reduced kinase activity and reduced protein expression compared to wildtype (PMID: 33944995). Based on the available evidence, the c.934C>T (p.Arg312Trp) variant is classified as likely pathogenic for Okur-Chung neurodevelopmental syndrome.

Comment:

The observed missense c.934C>T (p.Arg312Trp) variant in CSNK2A1 gene has been reported in multiple individuals affected CSNK2A1-related disorders (Owen et al., 2018; Deciphering Developmental Disorders Study, 2017; Chiu et al., 2018). The p.Arg312Trp variant is absent in the gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic (multiple submissions) / Likely Pathogenic. The amino acid change p.Arg312Trp in CSNK2A1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates.The amino acid Arg at position 312 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. Additional functional studies will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as Likely Pathogenic.

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29383814, 28135719, 24395637, 11574463, 33944995, 31785789, 27048600, 29240241)

Comment:

Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-09-17 and interpreted as Pathogenic. Variant was initially reported on 2018-06-11 by GTR ID of laboratory name 26957. The reporting laboratory might also submit to ClinVar.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Okur-Chung neurodevelopmental syndrome-linked CK2α variants have reduced kinase activity.	Dominguez I	Human genetics	2021	PMID: 33944995
Extending the phenotype associated with the CSNK2A1-related Okur-Chung syndrome-A clinical study of 11 individuals.	Owen CI	American journal of medical genetics. Part A	2018	PMID: 29383814
Okur-Chung neurodevelopmental syndrome: Eight additional cases with implications on phenotype and genotype expansion.	Chiu ATG	Clinical genetics	2018	PMID: 29240241
Prevalence and architecture of de novo mutations in developmental disorders.	Deciphering Developmental Disorders Study	Nature	2017	PMID: 28135719
De novo mutations in CSNK2A1 are associated with neurodevelopmental abnormalities and dysmorphic features.	Okur V	Human genetics	2016	PMID: 27048600
Presynaptic CK2 promotes synapse organization and stability by targeting Ankyrin2.	Bulat V	The Journal of cell biology	2014	PMID: 24395637
Crystal structure of human protein kinase CK2: insights into basic properties of the CK2 holoenzyme.	Niefind K	The EMBO journal	2001	PMID: 11574463

Text-mined citations for rs2018124491 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jul 23, 2024

ClinVar Genomic variation as it relates to human health

NM_177559.3(CSNK2A1):c.934C>T (p.Arg312Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs2018124491 ...