rs281865497

Variant names:

• chr16-66513786-A-G
• rs281865497
• NM_004614.5:c.644T>C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_004614.5(TK2):​c.644T>C​(p.Leu215Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,814 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L215I) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TK2 NM_004614.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.82
• Publications: 6 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 16 ACMG points.

• PM1: In a hotspot region, there are 5 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 chr16-66513787-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3897043.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.917
• PP5: Variant 16-66513786-A-G is Pathogenic according to our data. Variant chr16-66513786-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2736362.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.644T>C	p.Leu215Pro	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.644T>C	p.Leu215Pro	missense_variant	Exon 9 of 10	1	NM_004614.5	ENSP00000440898.2
ENSG00000260851	ENST00000561728.1	n.92T>C		non_coding_transcript_exon_variant	Exon 2 of 6	2		ENSP00000462196.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251252 AF XY: 0.00000736

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: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461814 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727206

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44718

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial disease Pathogenic:1

Apr 10, 2025

Genomenon, Inc, Genomenon, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

TK2 Leu215Pro (c.644T>C) is a missense variant that changes the amino acid at residue 215 from Leucine to Proline. It is also described as L257P in the literature. This variant has been observed in multiple probands affected with mitochondrial disease in the compound heterozygous state, with a pathogenic or likely pathogenic variant confirmed in trans in at least one proband (PMID:32572108;16504786) and was found to segregate with disease in an affected family (PMID:16504786). 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 Leu215Pro (c.644T>C) as a likely pathogenic variant. -

not provided Pathogenic:1

Dec 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 215 of the TK2 protein (p.Leu215Pro). This variant is present in population databases (rs281865497, gnomAD 0.0009%). This missense change has been observed in individual(s) with mitochondrial DNA depletion syndrome (PMID: 16504786). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Leu257Pro. 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%. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;.;D;.;.;.;.;D;.;.;.;D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.96	D;D;.;D;.;D;D;D;.;D;D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.4	M;.;M;.;.;.;.;.;.;.;.;.
PhyloP100		4.8
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-6.2	.;.;.;.;D;D;D;D;D;.;.;.
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0020	.;.;.;.;D;D;D;D;D;.;.;.
Sift4G	Uncertain	0.025	D;D;D;D;D;T;D;D;D;D;D;.
Polyphen		1.0	D;.;D;.;.;D;.;.;.;.;.;.
Vest4		0.91
MutPred		0.67		.;.;.;Loss of stability (P = 0.0272);.;.;.;.;.;.;.;.;
MVP		1.0
MPC		1.4
ClinPred		0.98	D
GERP RS		4.9
PromoterAI		-0.0049	Neutral
Varity_R		0.99
gMVP		0.87
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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

Other links and lift over

dbSNP: rs281865497; hg19: chr16-66547689;