rs137854429

Variant names:

• chr16-66531394-G-C
• rs137854429
• NM_004614.5:c.361C>G

Your query was ambiguous. Multiple possible variants found:

• chr16-66531394-G-C
• chr16-66531394-G-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_004614.5(TK2):​c.361C>G​(p.His121Asp) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H121N) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TK2 NM_004614.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.48
• Publications: 1 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

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 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 chr16-66531394-GC-TT is described in ClinVar as Pathogenic. ClinVar VariationId is 38986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant 16-66531394-G-C is Pathogenic according to our data. Variant chr16-66531394-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3778845.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.361C>G	p.His121Asp	missense_variant	Exon 5 of 10	ENST00000544898.6	NP_004605.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TK2	ENST00000544898.6	c.361C>G	p.His121Asp	missense_variant	Exon 5 of 10	1	NM_004614.5	ENSP00000440898.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

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 His121Asp (c.361C>G) is a missense variant that changes the amino acid at residue 121 from Histidine to Aspartic acid. This variant has been observed in a proband affected with mitochondrial disease in the compound heterozygous state (PMID:29602790). The presence of pathogenic missense variant(s) at the same amino acid position indicates that this residue is likely important for protein function. 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 His121Asp (c.361C>G) as a likely pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D;.;D;.;.;.;.;D;.;.;.;D;D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;.;D;.;D;D;D;.;D;D;D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.9	M;.;M;.;.;.;.;.;.;.;.;.;.
PhyloP100		5.5
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-7.5	.;.;.;.;D;D;D;D;D;.;.;.;.
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0040	.;.;.;.;D;D;D;D;D;.;.;.;.
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D;D;.;.
Polyphen		1.0	D;.;D;.;.;P;.;.;.;.;.;.;.
Vest4		0.82
MutPred		0.78		.;.;.;Loss of MoRF binding (P = 0.0439);.;.;.;.;.;.;.;.;.;
MVP		0.99
MPC		1.3
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.94
gMVP		0.97

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

Other links and lift over

dbSNP: rs137854429; hg19: chr16-66565297;