rs137886900

chr16-66517207-G-Achr16-66517207-G-Cchr16-66517207-G-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP3 PP5_Very_Strong

The NM_004614.5(TK2):c.547C>T(p.Arg183Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000781 in 1,613,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R183G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000077 (0 hom.)
• Consequence: TK2 NM_004614.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 5.18

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 15 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_004614.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-66517207-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 38991.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827
• PP5: Variant 16-66517207-G-A is Pathogenic according to our data. Variant chr16-66517207-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 38992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TK2	NM_004614.5	c.547C>T	p.Arg183Trp	missense_variant	8/10	ENST00000544898.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TK2	ENST00000544898.6	c.547C>T	p.Arg183Trp	missense_variant	8/10	1	NM_004614.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

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: 0.000661

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000107 AC: 27 AN: 251488 Hom.: 0 AF XY: 0.0000956 AC XY: 13 AN XY: 135920

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000693

Gnomad NFE exome AF: 0.0000527

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000766 AC: 112 AN: 1461794 Hom.: 0 Cov.: 31 AF XY: 0.0000811 AC XY: 59 AN XY: 727206

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000842

Gnomad4 NFE exome AF: 0.0000504

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152128 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74292

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000661

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000956

Alfa AF: 0.0000439 Hom.: 0

Bravo AF: 0.0000378

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000906 AC: 11

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial DNA depletion syndrome, myopathic form Pathogenic:2 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	This variant has been previously reported as disease-causing and was found once in our laboratory in trans with another pathogenic variant (H121N) in a 16-year-old female with proximal muscle weakness. Heterozygotes are expected to be asymptomatic carriers. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 29, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 12, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 183 of the TK2 protein (p.Arg183Trp). This variant is present in population databases (rs137886900, gnomAD 0.08%). This missense change has been observed in individuals with mitochondrial DNA depletion syndrome (PMID: 15907288, 18819985, 29602790). It has also been observed to segregate with disease in related individuals. This variant is also known as c.673C>T, p.R225W. ClinVar contains an entry for this variant (Variation ID: 38992). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TK2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects TK2 function (PMID: 21937588). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg183 amino acid residue in TK2. Other variant(s) that disrupt this residue have been observed in individuals with TK2-related conditions (PMID: 12655576, 12682338, 19265691), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2012

- -

Mitochondrial DNA depletion syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Apr 13, 2023

Variant summary: TK2 c.547C>T (p.Arg183Trp) results in a non-conservative amino acid change located in the Deoxynucleoside kinase domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 251488 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TK2 causing Mitochondrial DNA Depletion Syndrome - TK2 Related (0.00011 vs 0.0011), allowing no conclusion about variant significance. c.547C>T has been reported in the literature in individuals affected with Mitochondrial DNA Depletion Syndrome - TK2 Related. These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.47
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D;.;D;.;.;.;.;D;.;.;.;D;D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Pathogenic	0.99	D;D;.;D;.;D;D;D;.;D;D;D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M;.;M;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.99	D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.32	T
REVEL	Pathogenic	0.92
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;.;.
Polyphen		1.0	D;.;D;.;.;D;.;.;.;.;.;.;.
Vest4		0.82
MutPred		0.73		.;.;.;Gain of catalytic residue at P228 (P = 0.0456);.;.;.;.;.;.;.;.;.;
MVP		1.0
MPC		1.1
ClinPred		0.88	D
GERP RS		5.6
Varity_R		0.84
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs137886900; hg19: chr16-66551110; COSMIC: COSV55284582; COSMIC: COSV55284582;