rs200121712

chr16-66549968-G-A

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.94C>T(p.Arg32Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00703 in 1,461,434 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R32Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0061 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0071 (50 hom.)
• Consequence: TK2 NM_004614.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.04

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023220778).
• BP6: Variant 16-66549968-G-A is Benign according to our data. Variant chr16-66549968-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 215261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-66549968-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00614 (934/152238) while in subpopulation NFE AF= 0.00785 (534/67986). AF 95% confidence interval is 0.0073. There are 4 homozygotes in gnomad4. There are 496 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TK2	NM_004614.5	c.94C>T	p.Arg32Trp	missense_variant	1/10	ENST00000544898.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TK2	ENST00000544898.6	c.94C>T	p.Arg32Trp	missense_variant	1/10	1	NM_004614.5	P1
	ENST00000563151.1	n.689G>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.00614 AC: 934 AN: 152130 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.0275

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.0258

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00785

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00727 AC: 483 AN: 66464 Hom.: 2 AF XY: 0.00665 AC XY: 249 AN XY: 37464

Gnomad AFR exome AF: 0.00280

Gnomad AMR exome AF: 0.00163

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00302

Gnomad FIN exome AF: 0.0238

Gnomad NFE exome AF: 0.00983

Gnomad OTH exome AF: 0.00542

GnomAD4 exome AF: 0.00713 AC: 9333 AN: 1309196 Hom.: 50 Cov.: 31 AF XY: 0.00694 AC XY: 4467 AN XY: 643454

Gnomad4 AFR exome AF: 0.00144

Gnomad4 AMR exome AF: 0.00164

Gnomad4 ASJ exome AF: 0.000803

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00305

Gnomad4 FIN exome AF: 0.0248

Gnomad4 NFE exome AF: 0.00748

Gnomad4 OTH exome AF: 0.00524

GnomAD4 genome AF: 0.00614 AC: 934 AN: 152238 Hom.: 4 Cov.: 33 AF XY: 0.00666 AC XY: 496 AN XY: 74436

Gnomad4 AFR AF: 0.00128

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00414

Gnomad4 FIN AF: 0.0258

Gnomad4 NFE AF: 0.00785

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00652 Hom.: 2

Bravo AF: 0.00391

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00571 AC: 22

ExAC AF: 0.00386 AC: 327

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 30, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 23, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	ENSG00000261519: BS2; TK2: BS2 -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 12, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 07, 2017	- -

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 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
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.010
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.;T;.;.;T;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.72	T;T;.;T;T;T;T
MetaRNN	Benign	0.0023	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.64	D
MutationAssessor	Benign	0.69	N;N;N;.;N;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Uncertain	0.68	T
REVEL	Uncertain	0.36
Sift4G	Uncertain	0.038	D;D;D;D;D;D;D
Polyphen		0.99	D;.;D;.;.;.;.
Vest4		0.17
MVP		0.98
MPC		0.37
ClinPred		0.057	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.091
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200121712; hg19: chr16-66583871; COSMIC: COSV105066454; COSMIC: COSV105066454;