rs187517309

Positions:

• chr16-66541869-G-A
• chr16-66541869-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004614.5(TK2):​c.231+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00739 in 1,613,988 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0048 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0077 (70 hom.)
• Consequence: TK2 NM_004614.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.243

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 16-66541869-G-A is Benign according to our data. Variant chr16-66541869-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 137668.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-66541869-G-A is described in Lovd as [Benign]. Variant chr16-66541869-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0048 (731/152266) while in subpopulation NFE AF= 0.0086 (585/68026). AF 95% confidence interval is 0.00802. There are 5 homozygotes in gnomad4. There are 302 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TK2	NM_004614.5	c.231+10C>T		intron_variant		ENST00000544898.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TK2	ENST00000544898.6	c.231+10C>T		intron_variant		1	NM_004614.5	P1

Frequencies

GnomAD3 genomes AF: 0.00480 AC: 731 AN: 152148 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00154

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.00210

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00434

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00860

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.00521 AC: 1311 AN: 251448 Hom.: 13 AF XY: 0.00553 AC XY: 751 AN XY: 135896

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00234

Gnomad ASJ exome AF: 0.00188

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00585

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00855

Gnomad OTH exome AF: 0.00423

GnomAD4 exome AF: 0.00766 AC: 11198 AN: 1461722 Hom.: 70 Cov.: 31 AF XY: 0.00770 AC XY: 5599 AN XY: 727154

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.00250

Gnomad4 ASJ exome AF: 0.00142

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00552

Gnomad4 FIN exome AF: 0.000711

Gnomad4 NFE exome AF: 0.00906

Gnomad4 OTH exome AF: 0.00674

GnomAD4 genome AF: 0.00480 AC: 731 AN: 152266 Hom.: 5 Cov.: 32 AF XY: 0.00406 AC XY: 302 AN XY: 74442

Gnomad4 AFR AF: 0.00154

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00435

Gnomad4 FIN AF: 0.000472

Gnomad4 NFE AF: 0.00860

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.00487 Hom.: 2

Bravo AF: 0.00483

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 02, 2016	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 25, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 11, 2013	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	Athena Diagnostics	Dec 31, 2019	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Mitochondrial DNA depletion syndrome, myopathic form Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 08, 2016	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

TK2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 02, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Mitochondrial DNA depletion syndrome, myopathic form;C4310734:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 21, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.3
DANN	Benign	0.65

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

Publications

LitVar

Other links and lift over

dbSNP: rs187517309; hg19: chr16-66575772;