ClinVar Genomic variation as it relates to human health
NM_001163435.3(TBCK):c.1897+1G>A
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001163435.3(TBCK):c.1897+1G>A
Variation ID: 183338 Accession: VCV000183338.32
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4q24 4: 106194717 (GRCh38) [ NCBI UCSC ] 4: 107115874 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Mar 16, 2015 Apr 6, 2024 Mar 17, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001163435.3:c.1897+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001163435.2:c.[1897+1G>A] NM_001163436.4:c.1897+1G>A splice donor NM_001163437.3:c.1780+1G>A splice donor NM_001290768.2:c.1381+1G>A splice donor NM_033115.5:c.1708+1G>A splice donor NC_000004.12:g.106194717C>T NC_000004.11:g.107115874C>T NG_034057.3:g.126967G>A LRG_836:g.126967G>A LRG_836t1:c.1897+1G>A - Protein change
- Other names
- 1897+1G-A
- Canonical SPDI
- NC_000004.12:106194716:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD) 0.00002
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 | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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. |
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TBCK | - | - |
GRCh38 GRCh37 |
783 | 803 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Likely pathogenic (1) |
no assertion criteria provided
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Dec 1, 2014 | RCV000162173.2 | |
Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Mar 17, 2024 | RCV000210876.13 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 10, 2021 | RCV001814075.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 25, 2024 | RCV002516437.2 |
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
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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
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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
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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. |
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Pathogenic
(Dec 19, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hypotonia, infantile, with psychomotor retardation and characteristic facies 3
Affected status: yes
Allele origin:
unknown
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Baylor Genetics
Accession: SCV001522066.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
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Pathogenic
(Jul 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Abnormality of the nervous system
Affected status: yes
Allele origin:
germline
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Kariminejad - Najmabadi Pathology & Genetics Center
Accession: SCV001755214.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Hypotonia, infantile, with psychomotor retardation and characteristic facies 3
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV002072920.1
First in ClinVar: Feb 03, 2022 Last updated: Feb 03, 2022 |
Comment:
The splice donor variant c.1897+1G>A in TBCK (NM_001163435.3) has been previously reported in affected patients (Bhoj E et al). The variant has been submitted to … (more)
The splice donor variant c.1897+1G>A in TBCK (NM_001163435.3) has been previously reported in affected patients (Bhoj E et al). The variant has been submitted to ClinVar as Pathogenic/Likely pathogenic. The c.1897+1G>A variant is observed in 2/29,354 (0.0068%) alleles from individuals of Latino background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant affects an invariant splice nucleotide and is predicted to cause loss of function. Loss of function mutations have been reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Myopathy (present)
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Pathogenic
(May 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hypotonia, infantile, with psychomotor retardation and characteristic facies 3
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002521425.1
First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Canonical splice site: predicted to alter splicing … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000183338). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Global developmental delay (present) , Seizure (present) , Abnormal facial shape (present) , Cystic renal dysplasia (present) , Blindness (present) , Increased circulating lactate concentration … (more)
Global developmental delay (present) , Seizure (present) , Abnormal facial shape (present) , Cystic renal dysplasia (present) , Blindness (present) , Increased circulating lactate concentration (present) , Increased serum pyruvate (present) (less)
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Pathogenic
(Feb 07, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hypotonia, infantile, with psychomotor retardation and characteristic facies 3
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002018935.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Mar 17, 2024)
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criteria provided, single submitter
Method: research
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Hypotonia, infantile, with psychomotor retardation and characteristic facies 3
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004804719.2
First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024 |
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Pathogenic
(Jan 25, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV003525523.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects a donor splice site in intron 21 of the TBCK gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more)
This sequence change affects a donor splice site in intron 21 of the TBCK gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TBCK are known to be pathogenic (PMID: 27040692, 30103036). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individual(s) with TBCK-related conditions (PMID: 25558065). This variant is also known as c.1708+1G>A. ClinVar contains an entry for this variant (Variation ID: 183338). Studies have shown that disruption of this splice site alters TBCK gene expression (PMID: 27040691). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Dec 01, 2014)
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no assertion criteria provided
(research)
Method: research
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Global developmental delay
Epilepsy Dysmorphism Hypotonia Delayed reflexes Ventral septal defect
Affected status: yes
Allele origin:
germline
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Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre
Accession: SCV000196459.1
First in ClinVar: Mar 16, 2015 Last updated: Mar 16, 2015 |
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Pathogenic
(Jan 13, 2015)
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no assertion criteria provided
Method: literature only
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HYPOTONIA, INFANTILE, WITH PSYCHOMOTOR RETARDATION AND CHARACTERISTIC FACIES 3
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000267181.3
First in ClinVar: Apr 23, 2016 Last updated: Dec 09, 2018 |
Comment on evidence:
In 2 sibs, born of consanguineous Saudi parents (family 10DG1670), with infantile hypotonia with psychomotor retardation and characteristic facies-3 (IHPRF3; 616900), Alazami et al. (2015) … (more)
In 2 sibs, born of consanguineous Saudi parents (family 10DG1670), with infantile hypotonia with psychomotor retardation and characteristic facies-3 (IHPRF3; 616900), Alazami et al. (2015) identified a homozygous c.1708+1G-A (c.1708+1G-A, NM_033115) transition in the TBCK gene, predicted to result in a splicing defect. The mutation was found by whole-exome sequencing and segregated with the disorder in the family. Functional studies and studies of patient cells were not performed. The patients had severe global developmental delay, epilepsy, dysmorphic features, hypotonia, and diffuse brain atrophy. The patients were part of a large cohort of 143 multiplex consanguineous families with various neurodevelopmental disorders who underwent whole-exome sequencing. Bhoj et al. (2016) provided follow-up of the sibs reported by Alazami et al. (2015), and stated that the mutation was a homozygous c.1897+1G-A transition (c.1897+1G-A, NM_001163435.2) predicted to result in a frameshift. One of the patients died at age 5 years. Patient cells showed no detectable TBCK protein, consistent with a loss of function. The variant was found at a low frequency (0.000008319) in the ExAC database. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Further delineation of TBCK - Infantile hypotonia with psychomotor retardation and characteristic facies type 3. | Zapata-Aldana E | European journal of medical genetics | 2019 | PMID: 30103036 |
Recessive Inactivating Mutations in TBCK, Encoding a Rab GTPase-Activating Protein, Cause Severe Infantile Syndromic Encephalopathy. | Chong JX | American journal of human genetics | 2016 | PMID: 27040692 |
Mutations in TBCK, Encoding TBC1-Domain-Containing Kinase, Lead to a Recognizable Syndrome of Intellectual Disability and Hypotonia. | Bhoj EJ | American journal of human genetics | 2016 | PMID: 27040691 |
Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families. | Alazami AM | Cell reports | 2015 | PMID: 25558065 |
Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
Text-mined citations for rs374319146 ...
HelpRecord last updated Apr 06, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.