16-66517179-C-T

Variant names:

• chr16-66517179-C-T
• rs281865496
• NM_004614.5:c.575G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_004614.5(TK2):​c.575G>A​(p.Arg192Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,874 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R192G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TK2 NM_004614.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 5.79
• Publications: 17 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 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

ENSG00000260851 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 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 chr16-66517180-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3778858.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 16-66517179-C-T is Pathogenic according to our data. Variant chr16-66517179-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 38994.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	c.575G>A	p.Arg192Lys	missense_variant	Exon 8 of 10	ENST00000544898.6	NP_004605.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TK2	ENST00000544898.6	c.575G>A	p.Arg192Lys	missense_variant	Exon 8 of 10	1	NM_004614.5	ENSP00000440898.2
ENSG00000260851	ENST00000561728.1	n.23G>A		non_coding_transcript_exon_variant	Exon 1 of 6	2		ENSP00000462196.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251492 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461874 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

May 18, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R192K variant in the TK2 gene has been reported previously in association with mitochondrial DNA depletion syndrome in an affected individual who was compound heterozygous for the R192K variant and another disease-causing variant (Wang et al., 2005). The R192K variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R192K variant is conservative amino acid substitution and occurs at a position that is conserved across species. Functional studies of the R192K variant demonstrated residual enzyme activity of 4% compared to wild type (Wang et al., 2005). We interpret R192K as a pathogenic variant. -

Aug 05, 2022

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 lysine, which is basic and polar, at codon 192 of the TK2 protein (p.Arg192Lys). This variant is present in population databases (rs281865496, gnomAD 0.003%). This missense change has been observed in individuals with mitochondrial DNA depletion syndrome (PMID: 15639197, 25948719, 29735374, 31125140). This variant is also known as R161K. ClinVar contains an entry for this variant (Variation ID: 38994). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TK2 function (PMID: 15639197). This variant disrupts the p.Arg192 amino acid residue in TK2. Other variant(s) that disrupt this residue have been observed in individuals with TK2-related conditions (PMID: 27660820), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Mitochondrial disease Pathogenic:1

Apr 10, 2025

Genomenon, Inc, Genomenon, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

TK2 Arg192Lys (c.575G>A) is a missense variant that changes the amino acid at residue 192 from Arginine to Lysine. It is also described as R161K and R234K in the literature. This variant has been observed in multiple probands affected with mitochondrial disease in the compound heterozygous state (PMID:31125140;29735374;25948719;15639197) and was found to segregate with disease in an affected family (PMID:29735374). Experimental studies have shown that this variant results in a significant reduction of catalytic activity compared to the wild type (PMID:15639197). 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 Arg192Lys (c.575G>A) as a pathogenic variant. -

Mitochondrial DNA depletion syndrome, myopathic form Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;.;D;.;.;.;.;D;.;.;.;D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Benign	0.75	D
LIST_S2	Pathogenic	0.97	D;D;.;D;.;D;D;D;.;D;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H;.;H;.;.;.;.;.;.;.;.;.
PhyloP100		5.8
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.0	.;.;.;.;D;D;D;D;D;.;.;.
REVEL	Pathogenic	0.95
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		0.96
MutPred		0.95		.;.;.;Gain of disorder (P = 0.0649);.;.;.;.;.;.;.;.;
MVP		1.0
MPC		1.1
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.94
gMVP		0.85
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs281865496; hg19: chr16-66551082;