chr16-66513795-A-T

Variant names:

• chr16-66513795-A-T
• rs137854430
• NM_004614.5:c.635T>A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_004614.5(TK2):​c.635T>A​(p.Ile212Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TK2 NM_004614.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.54

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]

ENSG00000260851 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 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, 0.96
• PP5: Variant 16-66513795-A-T is Pathogenic according to our data. Variant chr16-66513795-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 12709.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TK2	NM_004614.5	c.635T>A	p.Ile212Asn	missense_variant	Exon 9 of 10	ENST00000544898.6	NP_004605.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TK2	ENST00000544898.6	c.635T>A	p.Ile212Asn	missense_variant	Exon 9 of 10	1	NM_004614.5	ENSP00000440898.2
ENSG00000260851	ENST00000561728.1	n.83T>A		non_coding_transcript_exon_variant	Exon 2 of 6	2		ENSP00000462196.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial disease Pathogenic:1

Apr 10, 2025

Genomenon, Inc, Genomenon, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

TK2 Ile212Asn (c.635T>A) is a missense variant that changes the amino acid at residue 212 from Isoleucine to Asparagine. It is also described as I254N and Ile181Asn 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 at least one proband (PMID:11687801;19815440;23932787). Experimental studies have shown that this variant results in a significant reduction in catalytic activity compared to the wild type (PMID:12493767). 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 Ile212Asn (c.635T>A) as a pathogenic variant. -

Mitochondrial DNA depletion syndrome, myopathic form Pathogenic:1

Feb 28, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Aug 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 212 of the TK2 protein (p.Ile212Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with mitochondrial DNA depletion syndrome (PMID: 11687801, 16908738, 29602790). ClinVar contains an entry for this variant (Variation ID: 12709). 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 80%. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	D;.;D;.;.;.;.;D;.;.;.;D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.97	D;D;.;D;.;D;D;D;.;D;D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;.;M;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-6.2	.;.;.;.;D;D;D;D;D;.;.;.
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	.;.;.;.;D;D;D;D;D;.;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D;D;D;.
Polyphen		1.0	D;.;D;.;.;D;.;.;.;.;.;.
Vest4		0.98
MutPred		0.83		.;.;.;Loss of stability (P = 0.0081);.;.;.;.;.;.;.;.;
MVP		0.98
MPC		1.5
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.95
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs137854430; hg19: chr16-66547698;