ClinVar Genomic variation as it relates to human health
NM_001382273.1(TNK2):c.1957G>A (p.Val653Met)
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.
Uncertain significance(1); Likely benign(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001382273.1(TNK2):c.1957G>A (p.Val653Met)
Variation ID: 88849 Accession: VCV000088849.6
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3q29 3: 195868341 (GRCh38) [ NCBI UCSC ] 3: 195595212 (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 Nov 28, 2013 Mar 16, 2024 May 15, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001382273.1:c.1957G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001369202.1:p.Val653Met missense NM_001010938.2:c.2029G>A NP_001010938.2:p.Val677Met missense NM_001308046.2:c.2008G>A NP_001294975.1:p.Val670Met missense NM_001382271.1:c.2008G>A NP_001369200.1:p.Val670Met missense NM_001382272.1:c.2029G>A NP_001369201.1:p.Val677Met missense NM_001382274.1:c.1957G>A NP_001369203.1:p.Val653Met missense NM_001382275.1:c.2053G>A NP_001369204.1:p.Val685Met missense NM_001386164.1:c.1912G>A NP_001373093.1:p.Val638Met missense NM_001387707.1:c.2053G>A NP_001374636.1:p.Val685Met missense NM_001387708.1:c.1984G>A NP_001374637.1:p.Val662Met missense NM_001387709.1:c.1912G>A NP_001374638.1:p.Val638Met missense NM_001387710.1:c.1912G>A NP_001374639.1:p.Val638Met missense NM_001387711.1:c.1912G>A NP_001374640.1:p.Val638Met missense NM_001387712.1:c.1912G>A NP_001374641.1:p.Val638Met missense NM_001387713.1:c.1912G>A NP_001374642.1:p.Val638Met missense NM_001387714.1:c.1912G>A NP_001374643.1:p.Val638Met missense NM_001387715.1:c.1984G>A NP_001374644.1:p.Val662Met missense NM_001387716.1:c.1957G>A NP_001374645.1:p.Val653Met missense NM_001387717.1:c.1957G>A NP_001374646.1:p.Val653Met missense NM_001387718.1:c.1957G>A NP_001374647.1:p.Val653Met missense NM_001387719.1:c.1912G>A NP_001374648.1:p.Val638Met missense NM_001387720.1:c.1912G>A NP_001374649.1:p.Val638Met missense NM_001387721.1:c.1912G>A NP_001374650.1:p.Val638Met missense NM_005781.5:c.1912G>A NP_005772.3:p.Val638Met missense NR_170678.1:n.2204G>A non-coding transcript variant NR_170679.1:n.2508G>A non-coding transcript variant NR_170680.1:n.2215G>A non-coding transcript variant NR_170681.1:n.2170G>A non-coding transcript variant NR_170682.1:n.2482G>A non-coding transcript variant NR_170683.1:n.2437G>A non-coding transcript variant NR_170684.1:n.1850G>A non-coding transcript variant NR_170685.1:n.2353G>A non-coding transcript variant NR_170686.1:n.2221G>A non-coding transcript variant NR_170687.1:n.2196G>A non-coding transcript variant NR_170688.1:n.2437G>A non-coding transcript variant NR_170689.1:n.1951G>A non-coding transcript variant NR_170690.1:n.1762G>A non-coding transcript variant NR_170691.1:n.2109G>A non-coding transcript variant NR_170692.1:n.1719G>A non-coding transcript variant NC_000003.12:g.195868341C>T NC_000003.11:g.195595212C>T NG_029779.1:g.45669G>A Q07912:p.Val638Met - Protein change
- V638M, V677M, V670M, V653M, V662M, V685M
- Other names
- V716M
- Canonical SPDI
- NC_000003.12:195868340: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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0.00260 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00063
Trans-Omics for Precision Medicine (TOPMed) 0.00095
1000 Genomes Project 30x 0.00250
1000 Genomes Project 0.00260
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
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. |
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TNK2 | - | - |
GRCh38 GRCh37 |
310 | 368 |
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. |
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Uncertain significance (1) |
no assertion criteria provided
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Sep 1, 2013 | RCV000074437.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 1, 2016 | RCV000210440.1 | |
Likely benign (1) |
criteria provided, single submitter
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- | RCV001258313.2 | |
Likely benign (1) |
criteria provided, single submitter
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May 15, 2023 | RCV002514326.2 | |
Likely benign (1) |
criteria provided, single submitter
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Nov 15, 2021 | RCV003925025.1 |
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. |
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Likely benign
(Nov 15, 2021)
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criteria provided, single submitter
Method: clinical testing
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TNK2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004754231.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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Uncertain significance
(Jan 01, 2016)
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criteria provided, single submitter
Method: research
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Parkinson disease
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine
Accession: SCV000266506.1
First in ClinVar: Apr 03, 2016 Last updated: Apr 03, 2016 |
Number of individuals with the variant: 2
Family history: yes
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Likely benign
(-)
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criteria provided, single submitter
Method: research
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Infantile epilepsy
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001435266.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Comment:
The homozygous p.Val716Met variant in TNK2 has been identified in 3 Belgian and Italian siblings from 1 family with infantile-onset epilepsy (PMID: 23686771), and has … (more)
The homozygous p.Val716Met variant in TNK2 has been identified in 3 Belgian and Italian siblings from 1 family with infantile-onset epilepsy (PMID: 23686771), and has been identified in >1% of South Asian chromosomes and 2 homozygotes by ExAC (http://gnomad.broadinstitute.org/). Furthermore, this is the first report of pathogenicity for a variant in this gene. In vitro functional studies provide some evidence that the p.Val716Met variant may slightly impact protein function (PMID: 23686771). However, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal recessive infantile-onset epilepsy. (less)
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Likely benign
(May 15, 2023)
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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: SCV002994382.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 28, 2024 |
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Uncertain significance
(Sep 01, 2013)
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no assertion criteria provided
Method: literature only
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VARIANT OF UNKNOWN SIGNIFICANCE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000108453.1
First in ClinVar: Nov 28, 2013 Last updated: Nov 28, 2013 |
Comment on evidence:
This variant is classified as a variant of unknown significance because its contribution to autosomal recessive infantile epilepsy has not been confirmed. In 3 sibs, … (more)
This variant is classified as a variant of unknown significance because its contribution to autosomal recessive infantile epilepsy has not been confirmed. In 3 sibs, born of unrelated Belgian Italian parents, with infantile-onset focal seizures followed by delayed psychomotor development, Hitomi et al. (2013) identified a homozygous c.2146G-T transversion in exon 13 of the TNK2 gene, resulting in a val716-to-met (V716M) substitution in a highly conserved region in the binding region of the E3 ubiquitin ligase NEDD4 (602278). The variant, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in 403 controls or in the Exome Variant Server database. Sequencing of the TNK2 gene in 3,140 mainly adult patients with epilepsy and 1,693 controls showed no further homozygotes, with very low frequencies of heterozygotes (0.002) in both groups. The unaffected parents were heterozygous for the V716M variant. Sanger sequencing of the coding region of TNK2 in 110 patients with infantile-onset epilepsy and intellectual disability identified no further homozygous mutations. Western blot analysis showed that the V716M protein was expressed similarly to wildtype, but the mutation disrupted the interaction of TNK2 with its ubiquitin ligases, thus leading to its loss of degradation by EGF (131530)-mediated activation. The patients had onset of refractory focal seizures between 19 and 35 months of age. Seizures were characterized by unresponsiveness, hypertonia, automatisms, and occasional secondary generalization. Significant speech and cognitive delay started soon after seizure onset, and 2 patients had autistic features. Brain MRI was normal and EEG unremarkable in all 3 children. Hitomi et al. (2013) postulated a gain-of-function pathogenic mechanism. (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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Mutations in TNK2 in severe autosomal recessive infantile onset epilepsy. | Hitomi Y | Annals of neurology | 2013 | PMID: 23686771 |
Text-mined citations for rs201407161 ...
HelpRecord last updated Mar 30, 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.