16-66512079-C-T

Variant names:

• chr16-66512079-C-T
• rs16956600
• NM_004614.5:c.700-13G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_004614.5(TK2):​c.700-13G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0955 in 1,610,742 control chromosomes in the GnomAD database, including 8,333 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1337 hom., cov: 33)
  • Exomes 𝑓: 0.093 (6996 hom.)
• Consequence: TK2 NM_004614.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.26
• Publications: 12 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: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 16-66512079-C-T is Benign according to our data. Variant chr16-66512079-C-T is described in ClinVar as Benign. ClinVar VariationId is 137664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.19 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TK2	NM_004614.5	c.700-13G>A		intron_variant	Intron 9 of 9	ENST00000544898.6	NP_004605.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TK2	ENST00000544898.6	c.700-13G>A		intron_variant	Intron 9 of 9	1	NM_004614.5	ENSP00000440898.2
ENSG00000260851	ENST00000561728.1	n.147+1652G>A		intron_variant	Intron 2 of 5	2		ENSP00000462196.1

Frequencies

GnomAD3 genomes AF: 0.121 AC: 18344 AN: 152080 Hom.: 1339 Cov.: 33

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.114

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.0729

Gnomad EAS AF: 0.164

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.0481

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0858

Gnomad OTH AF: 0.110

GnomAD2 exomes AF: 0.113 AC: 28176 AN: 248988 AF XY: 0.109

Gnomad AFR exome AF: 0.195

Gnomad AMR exome AF: 0.175

Gnomad ASJ exome AF: 0.0749

Gnomad EAS exome AF: 0.168

Gnomad FIN exome AF: 0.0503

Gnomad NFE exome AF: 0.0884

Gnomad OTH exome AF: 0.107

GnomAD4 exome AF: 0.0928 AC: 135414 AN: 1458544 Hom.: 6996 Cov.: 28 AF XY: 0.0927 AC XY: 67255 AN XY: 725878

African (AFR) AF: 0.201 AC: 6710 AN: 33428

American (AMR) AF: 0.174 AC: 7763 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0743 AC: 1940 AN: 26116

East Asian (EAS) AF: 0.152 AC: 6020 AN: 39680

South Asian (SAS) AF: 0.112 AC: 9682 AN: 86216

European-Finnish (FIN) AF: 0.0535 AC: 2858 AN: 53410

Middle Eastern (MID) AF: 0.0889 AC: 512 AN: 5760

European-Non Finnish (NFE) AF: 0.0846 AC: 93846 AN: 1108944

Other (OTH) AF: 0.101 AC: 6083 AN: 60272

GnomAD4 genome AF: 0.121 AC: 18358 AN: 152198 Hom.: 1337 Cov.: 33 AF XY: 0.118 AC XY: 8793 AN XY: 74404

African (AFR) AF: 0.194 AC: 8037 AN: 41510

American (AMR) AF: 0.130 AC: 1981 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0729 AC: 253 AN: 3470

East Asian (EAS) AF: 0.164 AC: 846 AN: 5172

South Asian (SAS) AF: 0.112 AC: 541 AN: 4824

European-Finnish (FIN) AF: 0.0481 AC: 510 AN: 10596

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0857 AC: 5831 AN: 68014

Other (OTH) AF: 0.111 AC: 234 AN: 2114

Alfa AF: 0.0971 Hom.: 3501

Bravo AF: 0.133

Asia WGS AF: 0.152 AC: 529 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Jul 01, 2011

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mitochondrial DNA depletion syndrome, myopathic form Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	12
DANN	Benign	0.77
PhyloP100		1.3
PromoterAI		-0.029	Neutral
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs16956600; hg19: chr16-66545982; COSMIC: COSV55283774; COSMIC: COSV55283774;