rs137886900

Variant names:

• chr16-66517207-G-A
• rs137886900
• NM_004614.5:c.547C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-66517207-G-A
• chr16-66517207-G-C
• chr16-66517207-G-T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP3 PP5_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R183Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000077 (0 hom.)
• Consequence: TK2 NM_004614.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 5.18
• Publications: 19 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 15 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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 chr16-66517207-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 38991.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 VariationId is 38992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TK2	NM_004614.5	MANE Select	c.547C>T	p.Arg183Trp	missense	Exon 8 of 10	NP_004605.4
	TK2	NM_001172645.2		c.493C>T	p.Arg165Trp	missense	Exon 7 of 9	NP_001166116.1
	TK2	NM_001172644.2		c.472C>T	p.Arg158Trp	missense	Exon 7 of 9	NP_001166115.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TK2	ENST00000544898.6	TSL:1 MANE Select	c.547C>T	p.Arg183Trp	missense	Exon 8 of 10	ENSP00000440898.2
	TK2	ENST00000451102.7	TSL:1	c.454C>T	p.Arg152Trp	missense	Exon 8 of 10	ENSP00000414334.4
	TK2	ENST00000527284.6	TSL:1	c.490C>T	p.Arg164Trp	missense	Exon 8 of 9	ENSP00000435312.2

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152128 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.000107 AC: 27 AN: 251488 AF XY: 0.0000956

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 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.: 0 Cov.: 31 AF XY: 0.0000811 AC XY: 59 AN XY: 727206

African (AFR) AF: 0.000119 AC: 4 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.000842 AC: 45 AN: 53416

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

European-Non Finnish (NFE) AF: 0.0000504 AC: 56 AN: 1111920

Other (OTH) AF: 0.0000993 AC: 6 AN: 60394

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152128 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74292

African (AFR) AF: 0.0000483 AC: 2 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000661 AC: 7 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68030

Other (OTH) AF: 0.000956 AC: 2 AN: 2092

Alfa AF: 0.0000959 Hom.: 0

Bravo AF: 0.0000378

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000906 AC: 11

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial DNA depletion syndrome, myopathic form Pathogenic:2 Other:1

Sep 01, 2017

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

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

not provided Pathogenic:2

Dec 24, 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 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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TK2 protein function with a positive predictive value of 95%. 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.

Jan 29, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3 Pathogenic:1

Jan 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Mitochondrial disease Pathogenic:1

Apr 10, 2025

Genomenon, Inc, Genomenon, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

TK2 Arg183Trp (c.547C>T) is a missense variant that changes the amino acid at residue 183 from Arginine to Tryptophan. It is also described as R225W in the literature. This variant has been observed in multiple probands affected with mitochondrial disease in both the homozygous and compound heterozygous state, with a pathogenic or likely pathogenic variant confirmed in trans in several of these probands (PMID:33013660;18819985;15907288;23932787;21937588). TK2 Arg183Trp was found to segregate with disease in affected families (PMID:15907288;21937588). Experimental studies have shown that this variant results in a significant reduction of catalytic activity compared to the wild type (PMID:21937588). 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 Arg183Trp (c.547C>T) as a pathogenic variant.

Mitochondrial DNA depletion syndrome Pathogenic:1

Apr 13, 2023

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.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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		5.2
PrimateAI	Benign	0.32	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	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	D
GERP RS		5.6
Varity_R		0.84
gMVP		0.62
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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

Other links and lift over

dbSNP: rs137886900; hg19: chr16-66551110; COSMIC: COSV55284582; COSMIC: COSV55284582;