NM_004614.5:c.760C>A

Variant names:

• chr16-66512006-G-T
• rs281865498
• NM_004614.5:c.760C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004614.5(TK2):​c.760C>A​(p.Arg254Arg) variant causes a synonymous change. The variant allele was found at a frequency of 0.000000684 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TK2 NM_004614.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.83
• Publications: 0 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: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• autosomal recessive progressive external ophthalmoplegia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000260851 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TK2	NM_004614.5	MANE Select	c.760C>A	p.Arg254Arg	synonymous	Exon 10 of 10	NP_004605.4
	TK2	NM_001172645.2		c.706C>A	p.Arg236Arg	synonymous	Exon 9 of 9	NP_001166116.1	O00142-4
	TK2	NM_001172644.2		c.685C>A	p.Arg229Arg	synonymous	Exon 9 of 9	NP_001166115.1	O00142-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TK2	ENST00000544898.6	TSL:1 MANE Select	c.760C>A	p.Arg254Arg	synonymous	Exon 10 of 10	ENSP00000440898.2	O00142-1
	TK2	ENST00000451102.7	TSL:1	c.667C>A	p.Arg223Arg	synonymous	Exon 10 of 10	ENSP00000414334.4	O00142-2
	TK2	ENST00000527284.6	TSL:1	c.622C>A	p.Arg208Arg	synonymous	Exon 9 of 9	ENSP00000435312.2	A0A7P0PE46

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461886 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

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

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: 53416

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112010

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

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	13
DANN	Benign	0.67
PhyloP100		3.8
PromoterAI		0.0024	Neutral
Mutation Taster		=98/2	polymorphism

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: rs281865498; hg19: chr16-66545909;