rs137886900

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PP3PP5_Very_Strong

The NM_004614.5(TK2):c.547C>T(p.Arg183Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000781 in 1,613,922 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 Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000077 ( 0 hom. )

Consequence

TK2
NM_004614.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.18

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 links:

ENSG00000260851 (HGNC:):

ENSG00000260851 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1

In a chain Thymidine kinase 2, mitochondrial (size 231) in uniprot entity KITM_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_004614.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.827

PP5

Variant 16-66517207-G-A is Pathogenic according to our data. Variant chr16-66517207-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 38992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TK2	NM_004614.5 linkuse as main transcript	c.547C>T	p.Arg183Trp	missense_variant	8/10	ENST00000544898.6	NP_004605.4	O00142-1Q8IZR3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TK2	ENST00000544898.6 linkuse as main transcript	c.547C>T	p.Arg183Trp	missense_variant	8/10	1	NM_004614.5	ENSP00000440898.2		O00142-1
ENSG00000260851	ENST00000561728.1 linkuse as main transcript	n.-6C>T		upstream_gene_variant		2		ENSP00000462196.1		J3KRW8

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.000661

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000107

AC:

AN:

251488

Hom.:

AF XY:

0.0000956

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000693

Gnomad NFE exome

AF:

0.0000527

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000766

AC:

112

AN:

1461794

Hom.:

Cov.:

AF XY:

0.0000811

AC XY:

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000842

Gnomad4 NFE exome

AF:

0.0000504

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152128

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000661

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000956

Alfa

AF:

0.0000439

Hom.:

Bravo

AF:

0.0000378

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000906

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mitochondrial DNA depletion syndrome, myopathic form

Pathogenic:2Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	This variant has been previously reported as disease-causing and was found once in our laboratory in trans with another pathogenic variant (H121N) in a 16-year-old female with proximal muscle weakness. Heterozygotes are expected to be asymptomatic carriers. -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 183 of the TK2 protein (p.Arg183Trp). This variant is present in population databases (rs137886900, gnomAD 0.08%). This missense change has been observed in individuals with mitochondrial DNA depletion syndrome (PMID: 15907288, 18819985, 29602790). It has also been observed to segregate with disease in related individuals. This variant is also known as c.673C>T, p.R225W. ClinVar contains an entry for this variant (Variation ID: 38992). 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: 21937588). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg183 amino acid residue in TK2. Other variant(s) that disrupt this residue have been observed in individuals with TK2-related conditions (PMID: 12655576, 12682338, 19265691), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 29, 2022	- -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2012

- -

Mitochondrial DNA depletion syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Apr 13, 2023

Variant summary: TK2 c.547C>T (p.Arg183Trp) results in a non-conservative amino acid change located in the Deoxynucleoside kinase domain 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 0.00011 in 251488 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TK2 causing Mitochondrial DNA Depletion Syndrome - TK2 Related (0.00011 vs 0.0011), allowing no conclusion about variant significance. c.547C>T has been reported in the literature in individuals affected with Mitochondrial DNA Depletion Syndrome - TK2 Related. These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

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

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.78

LIST_S2

Pathogenic

0.99

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

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.83

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.0

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

PrimateAI

Benign

0.32

PROVEAN

Pathogenic

-5.9

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

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.82

MutPred

0.73

.;.;.;Gain of catalytic residue at P228 (P = 0.0456);.;.;.;.;.;.;.;.;.;

MVP

1.0

MPC

1.1

ClinPred

0.88

GERP RS

5.6

Varity_R

0.84

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over