16-66531418-C-CAT
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_004614.5(TK2):c.335_336dupAT(p.Val113MetfsTer20) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,196 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Y112Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Consequence
TK2
NM_004614.5 frameshift
NM_004614.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -1.55
Publications
1 publications found
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]
TK2 Gene-Disease associations (from GenCC):
- mitochondrial diseaseInheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
- mitochondrial DNA depletion syndrome, myopathic formInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae), G2P
- autosomal recessive progressive external ophthalmoplegiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 12 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 16-66531418-C-CAT is Pathogenic according to our data. Variant chr16-66531418-C-CAT is described in ClinVar as Pathogenic. ClinVar VariationId is 3778866.Status of the report is criteria_provided_single_submitter, 1 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_004614.5. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TK2 | NM_004614.5 | MANE Select | c.335_336dupAT | p.Val113MetfsTer20 | frameshift | Exon 5 of 10 | NP_004605.4 | ||
| TK2 | NM_001172645.2 | c.281_282dupAT | p.Val95MetfsTer20 | frameshift | Exon 4 of 9 | NP_001166116.1 | O00142-4 | ||
| TK2 | NM_001172644.2 | c.260_261dupAT | p.Val88MetfsTer20 | frameshift | Exon 4 of 9 | NP_001166115.1 | O00142-3 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TK2 | ENST00000544898.6 | TSL:1 MANE Select | c.335_336dupAT | p.Val113MetfsTer20 | frameshift | Exon 5 of 10 | ENSP00000440898.2 | O00142-1 | |
| TK2 | ENST00000451102.7 | TSL:1 | c.242_243dupAT | p.Val82MetfsTer20 | frameshift | Exon 5 of 10 | ENSP00000414334.4 | O00142-2 | |
| TK2 | ENST00000527284.6 | TSL:1 | c.278_279dupAT | p.Val94fs | frameshift | Exon 5 of 9 | ENSP00000435312.2 | A0A7P0PE46 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152196Hom.: 0 Cov.: 32 show subpopulations
GnomAD3 genomes
AF:
AC:
1
AN:
152196
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
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Gnomad OTH
AF:
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome 0.00000657 AC: 1AN: 152196Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74346 show subpopulations ⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
GnomAD4 genome
AF:
AC:
1
AN:
152196
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
74346
show subpopulations
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
41450
American (AMR)
AF:
AC:
1
AN:
15282
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3472
East Asian (EAS)
AF:
AC:
0
AN:
5196
South Asian (SAS)
AF:
AC:
0
AN:
4826
European-Finnish (FIN)
AF:
AC:
0
AN:
10604
Middle Eastern (MID)
AF:
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
AC:
0
AN:
68044
Other (OTH)
AF:
AC:
0
AN:
2094
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.375
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic
Revision:criteria provided, single submitter
Pathogenic
VUS
Benign
Condition
1
-
-
Mitochondrial disease (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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