rs281865493

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1PM2PM5PP5_Very_Strong

The NM_004614.5(TK2):c.388C>T(p.Arg130Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000347 in 1,613,766 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R130Q) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

TK2
NM_004614.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6O:1

Conservation

PhyloP100: 3.76

Publications

15 publications found

Variant links:

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 disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
mitochondrial DNA depletion syndrome, myopathic form
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
autosomal recessive progressive external ophthalmoplegia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TK2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_004614.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-66529054-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 38989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP5

Variant 16-66529055-G-A is Pathogenic according to our data. Variant chr16-66529055-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 38988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TK2	NM_004614.5 link	c.388C>T	p.Arg130Trp	missense_variant	Exon 6 of 10	ENST00000544898.6	NP_004605.4	O00142-1Q8IZR3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TK2	ENST00000544898.6 link	c.388C>T	p.Arg130Trp	missense_variant	Exon 6 of 10	1	NM_004614.5	ENSP00000440898.2		O00142-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000755

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000756

AC:

AN:

251236

AF XY:

0.0000663

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000745

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000308

AC:

AN:

1461660

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

727134

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.000638

AC:

AN:

53254

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000630

AC:

AN:

1111954

Other (OTH)

AF:

0.0000331

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.441

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152106

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74300

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41422

American (AMR)

AF:

0.00

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000755

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000294

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 16, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies found this variant is associated with significantly reduced enzyme activity (PMID: 20083405); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(R172W); This variant is associated with the following publications: (PMID: 20083405, 18819985, no PMID, 31060578, 29602790, 23230576, 32827528, 34426522, 31589614, 34973561) -

Apr 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 130 of the TK2 protein (p.Arg130Trp). This variant is present in population databases (rs281865493, gnomAD 0.08%). This missense change has been observed in individual(s) with mitochondrial DNA depletion syndrome (PMID: 20083405, 29602790). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 38988). 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 expected to disrupt TK2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects TK2 function (PMID: 20083405). For these reasons, this variant has been classified as Pathogenic. -

Mitochondrial DNA depletion syndrome, myopathic form

Pathogenic:1Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mitochondrial disease

Pathogenic:1

Apr 10, 2025

Genomenon, Inc, Genomenon, Inc

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

TK2 Arg130Trp (c.388C>T) is a missense variant that changes the amino acid at residue 130 from Arginine to Tryptophan. It is also described as R172W in the literature. This variant has been observed in multiple probands affected with mitochondrial disease in both the homozygous and compound heterozygous state (PMID:34973561;31060578;29602790;18819985). TK2 Arg130Trp was found to segregate with disease in an affected family (PMID:18819985). Experimental studies have shown that this variant results in a significant reduction in catalytic activity compared to the wild type (PMID:20391188;20083405). This variant is not present at a significant frequency in gnomAD and in silico models agree that this variant is possibly or probably damaging. In conclusion, we classify TK2 Arg130Trp (c.388C>T) as a pathogenic variant. -

Mitochondrial DNA depletion syndrome

Pathogenic:1

Nov 13, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TK2 c.388C>T (p.Arg130Trp) 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 7.6e-05 in 251236 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TK2 causing Mitochondrial DNA Depletion Syndrome - TK2 Related (7.6e-05 vs 0.0011), allowing no conclusion about variant significance. c.388C>T has been reported in the literature in multiple individuals affected with Mitochondrial DNA Depletion Syndrome - TK2 Related (e.g. Lesko_2010, Garone_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in <4% of normal activity (Lesko_2010). The following publications have been ascertained in the context of this evaluation (PMID: 20083405, 29602790). ClinVar contains an entry for this variant (Variation ID: 38988). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

D;.;D;.;.;.;.;D;.;.;.;D;D

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.98

D;D;.;D;.;D;D;D;.;D;D;D;D

M_CAP

Uncertain

0.27

MetaRNN

Uncertain

0.67

D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.86

MutationAssessor

Pathogenic

3.1

M;.;M;.;.;.;.;.;.;.;.;.;.

PhyloP100

3.8

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-6.6

.;.;.;.;D;D;D;D;D;.;.;.;.

REVEL

Pathogenic

0.83

Sift

Pathogenic

0.0

.;.;.;.;D;D;D;D;D;.;.;.;.

Sift4G

Uncertain

0.0030

D;D;D;D;D;D;D;D;D;D;D;.;.

Polyphen

1.0

D;.;D;.;.;D;.;.;.;.;.;.;.

Vest4

0.93

MutPred

0.58

.;.;.;Loss of disorder (P = 0.005);.;.;.;.;.;.;.;.;.;

MVP

1.0

MPC

1.2

ClinPred

0.87

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.92

gMVP

0.82

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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rs281865493

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over