rs281865507
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PP5_Very_Strong
The NM_004614.5(TK2):c.360_361delinsAA(p.His121Asn) variant causes a missense change. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R120R) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Consequence
TK2
NM_004614.5 missense
NM_004614.5 missense
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.48
Genes affected
TK2 (HGNC:11831): (thymidine kinase 2) This gene encodes a deoxyribonucleoside kinase that specifically phosphorylates thymidine, deoxycytidine, and deoxyuridine. The encoded enzyme localizes to the mitochondria and is required for mitochondrial DNA synthesis. Mutations in this gene are associated with a myopathic form of mitochondrial DNA depletion syndrome. Alternate splicing results in multiple transcript variants encoding distinct isoforms, some of which lack transit peptide, so are not localized to mitochondria. [provided by RefSeq, Dec 2012]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_004614.5
PP5
?
Variant 16-66531394-GC-TT is Pathogenic according to our data. Variant chr16-66531394-GC-TT is described in ClinVar as [Pathogenic]. Clinvar id is 38986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TK2 | NM_004614.5 | c.360_361delinsAA | p.His121Asn | missense_variant | 5/10 | ENST00000544898.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TK2 | ENST00000544898.6 | c.360_361delinsAA | p.His121Asn | missense_variant | 5/10 | 1 | NM_004614.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Mitochondrial DNA depletion syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 24, 2023 | Variant summary: TK2 c.360_361delinsAA (p.His121Asn) results in a conservative amino acid change located in the Deoxynucleoside kinase domain (IPR031314) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 250910 control chromosomes. This frequency is not higher than estimated for a pathogenic variant in TK2 causing Mitochondrial DNA Depletion Syndrome - TK2 Related (0.00012 vs 0.0011), allowing no conclusion about variant significance. c.360_361delinsAA has been reported in the literature in multiple individuals affected with Mitochondrial DNA Depletion Syndrome - TK2 Related (Saada_2001, Oskoui_2006, Jou_2019, etc.). These data indicate that the variant is very likely to be associated with disease. Experimental evidence demonstrated the variant affects protein function (Saada_2001, Wang_2003). One ClinVar submitter has submitted clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 121 of the TK2 protein (p.His121Asn). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This missense change has been observed in individuals with mitochondrial DNA depletion syndrome (PMID: 11687801, 12391347, 16908738, 29602790). It has also been observed to segregate with disease in related individuals. This variant is also known as p.His90Asn. ClinVar contains an entry for this variant (Variation ID: 38986). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this missense change affects TK2 function (PMID: 12493767, 18446447). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at