rs281865489

chr16-66536981-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM1 PM2 PP5_Very_Strong BP4

The NM_004614.5(TK2):c.268C>T(p.Arg90Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000867 in 1,613,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: TK2 NM_004614.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.67

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a chain Thymidine kinase 2, mitochondrial (size 231) in uniprot entity KITM_HUMAN there are 48 pathogenic changes around while only 6 benign (89%) in NM_004614.5
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-66536981-G-A is Pathogenic according to our data. Variant chr16-66536981-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 38982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-66536981-G-A is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.2419571).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TK2	NM_004614.5	c.268C>T	p.Arg90Cys	missense_variant	4/10	ENST00000544898.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TK2	ENST00000544898.6	c.268C>T	p.Arg90Cys	missense_variant	4/10	1	NM_004614.5	P1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152002 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251486 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152002 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74234

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000945

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	TK2: PM3:Strong, PM2, PP4:Moderate -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 17, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25215937, 22345218, 31589614, 28217183, 29602790) -

Mitochondrial DNA depletion syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 11, 2023

Variant summary: TK2 c.268C>T (p.Arg90Cys) results in a non-conservative amino acid change located in the Deoxynucleoside kinase domain (IPR031314) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251486 control chromosomes (gnomAD). c.268C>T has been reported in the literature in individuals affected with Mitochondrial DNA Depletion Syndrome - TK2 Related who were compound heterozygous with other pathogenic variants (Behin_2012, Dominguez-Gonzalez_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22345218, 31125140, 26224072). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Mitochondrial DNA depletion syndrome, myopathic form Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 28, 2012

- -

Myopathy Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Neurologia y Psiquiatria, Clinica Alemana Santiago

Jul 15, 2022

We report a 50-year-old female with recurrent rhabdomyolysis, bilateral ptosis, and girdle limb weakness. Muscle biopsy presented frequent, red-raged fibers and dystrophic changes. The most severely affected muscles in magnetic resonance imaging (MRI) axial T1-weighted sequences were the gluteus maximus, sartorius and tensor fasciae latae muscles. We found a compound heterozygous mutation in TK2-gene (pathogenic mutation in [c.323C>T p.(Thr108Met)] and novel mutation in [c.268C>T p.(Arg90Cys)]). Deoxynucleoside therapy was offered. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	D;D;.;.;.;D
Eigen	Benign	-0.070
Eigen_PC	Benign	0.085
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.94	D;.;D;D;D;D
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.24	T;T;T;T;T;T
MetaSVM	Uncertain	0.031	D
MutationAssessor	Benign	1.8	L;L;.;.;.;.
MutationTaster	Benign	0.99	D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.40	T
REVEL	Uncertain	0.60
Sift4G	Benign	0.12	T;T;T;T;T;T
Polyphen		0.023	.;.;.;B;.;.
Vest4		0.30
MutPred		0.56		.;.;Loss of MoRF binding (P = 0.0355);.;.;.;
MVP		0.98
MPC		0.49
ClinPred		0.88	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs281865489; hg19: chr16-66570884;