rs281865494
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PS1_ModeratePM1PM2PP3PP5_Very_Strong
The NM_004614.5(TK2):c.416C>T(p.Ala139Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000483 in 1,613,916 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.
Frequency
Consequence
NM_004614.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TK2 | NM_004614.5 | c.416C>T | p.Ala139Val | missense_variant | 6/10 | ENST00000544898.6 | NP_004605.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TK2 | ENST00000544898.6 | c.416C>T | p.Ala139Val | missense_variant | 6/10 | 1 | NM_004614.5 | ENSP00000440898 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152122Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251356Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135866
GnomAD4 exome AF: 0.0000458 AC: 67AN: 1461794Hom.: 0 Cov.: 31 AF XY: 0.0000509 AC XY: 37AN XY: 727210
GnomAD4 genome AF: 0.0000723 AC: 11AN: 152122Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74306
ClinVar
Submissions by phenotype
not provided Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 05, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 139 of the TK2 protein (p.Ala139Val). This variant is present in population databases (rs281865494, gnomAD 0.004%). This missense change has been observed in individual(s) with mitochondrial DNA depletion syndrome (PMID: 16504786, 25446393). It has also been observed to segregate with disease in related individuals. This variant is also known as A181V. ClinVar contains an entry for this variant (Variation ID: 38990). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TK2 protein function with a negative predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 27, 2023 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 19, 2021 | Quantitative PCR analysis demonstrates marked depletion of mtDNA copy numbers in skeletal muscle from affected individuals (Knierim et al., 2015).; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; 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: 30609409, 29602790, 25446393, 27839525, 16504786) - |
Mitochondrial DNA depletion syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 14, 2022 | Variant summary: TK2 c.416C>T (p.Ala139Val) results in a non-conservative amino acid change located in the Deoxynucleoside kinase domain (IPR031314) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251356 control chromosomes (gnomAD). c.416C>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Mitochondrial DNA Depletion Syndrome - TK2 Related, and segregated with disease within families (e.g. Galbiati_2006, Knierim_2015, Wahbi_2015, Mazurova_2017). These data indicate that the variant is very likely to be associated with disease. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 21, 2017 | The p.Ala139Val (NM_004614.4 c.416C>T) (also referred to as p.Ala181Val in the l iterature) variant in TK2 has been reported in one compound heterozygous and one homozygous patients with mitochondrial DNA depletion syndrome and segregated in two affected siblings from two families (Galbiati 2006 and Knierim 2015). This variant has also been reported in ClinVar (Variation ID#5782). It has been ident ified in 5/126,712 of European chromosomes by the Genome Aggregation Database (g nomAD, http://gnomad.broadinstitute.org; dbSNP rs281865494). Although this varia nt has been seen in the general population, its frequency is low enough to be co nsistent with a recessive carrier frequency. Computational prediction tools and conservation analysis suggest that the p.Ala139Val variant may impact the protei n, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clin ical significance, the p.Ala139Val variant is likely pathogenic for TK2-related mitochondrial DNA depletion syndrome in an autosomal recessive manner based on i ts occurrence in individuals with this disease and low frequency in the general population. - |
TK2-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 28, 2023 | The TK2 c.416C>T variant is predicted to result in the amino acid substitution p.Ala139Val. This variant has been reported in individuals with autosomal recessive mitochondrial DNA depletion syndrome (referred to as c.542C>T, p.Ala181Val, Fig 3b, Galbiati et al. 2006. PubMed ID: 16504786; Knierim et al. 2014. PubMed ID: 25446393; Mazurova et al. 2016. PubMed ID: 27839525; Figure 2, Garone et al. 2018. PubMed ID: 29602790; Table S3, Ganapathy et al. 2019. PubMed ID: 31069529; Papadimas et al. 2020. PubMed ID: 32904881). This variant is reported in 0.0046% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-66562930-G-A). This variant is interpreted as pathogenic. - |
Mitochondrial DNA depletion syndrome, myopathic form;C4310734:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at