chr16-66512079-C-T

Position:

• chr16-66512079-C-T

Variant summary

Our verdict is Benign. Variant got -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

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 Benign. Variant got -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 id is 137664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-66512079-C-T is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
TK2	NM_004614.5	c.700-13G>A		intron_variant		ENST00000544898.6	NP_004605.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TK2	ENST00000544898.6	c.700-13G>A		intron_variant		1	NM_004614.5	ENSP00000440898.2
ENSG00000260851	ENST00000561728.1	n.147+1652G>A		intron_variant		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

GnomAD3 exomes AF: 0.113 AC: 28176 AN: 248988 Hom.: 1803 AF XY: 0.109 AC XY: 14682 AN XY: 134788

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 SAS exome AF: 0.115

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

Gnomad4 AFR exome AF: 0.201

Gnomad4 AMR exome AF: 0.174

Gnomad4 ASJ exome AF: 0.0743

Gnomad4 EAS exome AF: 0.152

Gnomad4 SAS exome AF: 0.112

Gnomad4 FIN exome AF: 0.0535

Gnomad4 NFE exome AF: 0.0846

Gnomad4 OTH exome AF: 0.101

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

Gnomad4 AFR AF: 0.194

Gnomad4 AMR AF: 0.130

Gnomad4 ASJ AF: 0.0729

Gnomad4 EAS AF: 0.164

Gnomad4 SAS AF: 0.112

Gnomad4 FIN AF: 0.0481

Gnomad4 NFE AF: 0.0857

Gnomad4 OTH AF: 0.111

Alfa AF: 0.0908 Hom.: 1490

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 01, 2011	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Mitochondrial DNA depletion syndrome, myopathic form Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs16956600; hg19: chr16-66545982; COSMIC: COSV55283774; COSMIC: COSV55283774;