rs138439950

Positions:

chr16-66541937-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The NM_004614.5(TK2):c.173A>G(p.Asn58Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,614,018 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

TK2
NM_004614.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 3.53

Variant links:

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]

TK2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a chain Thymidine kinase 2, mitochondrial (size 231) in uniprot entity KITM_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_004614.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.887

PP5

Variant 16-66541937-T-C is Pathogenic according to our data. Variant chr16-66541937-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 38978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-66541937-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TK2	NM_004614.5 link	c.173A>G	p.Asn58Ser	missense_variant	3/10	ENST00000544898.6	NP_004605.4	O00142-1Q8IZR3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TK2	ENST00000544898.6 link	c.173A>G	p.Asn58Ser	missense_variant	3/10	1	NM_004614.5	ENSP00000440898.2		O00142-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000437

AC:

AN:

251478

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000180

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74318

show subpopulations

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:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000288

Hom.:

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000494

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 2024	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, 24516753, 23932787, 29735374, 29602790, 33087887, 18508266, 30183064) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 58 of the TK2 protein (p.Asn58Ser). This variant is present in population databases (rs138439950, gnomAD 0.02%). This missense change has been observed in individual(s) with mitochondrial DNA depletion syndrome (PMID: 18508266, 29735374). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.N100S. ClinVar contains an entry for this variant (Variation ID: 38978). 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%. For these reasons, this variant has been classified as Pathogenic. -

Mitochondrial DNA depletion syndrome 2, myopathic form

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Oct 04, 2024

PM3(strong),PM2,PP3,PM1,PP2 -

Mitochondrial DNA depletion syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Sep 11, 2024

Variant summary: TK2 c.173A>G (p.Asn58Ser), also known as N100S, results in a conservative amino acid change located in the Deoxynucleoside kinase domain (IPR031314) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251478 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TK2 causing Mitochondrial DNA Depletion Syndrome - TK2 Related (4.4e-05 vs 0.0011). c.173A>G has been reported in the literature in the homozygous or presumed compound heterozygous state in multiple individuals affected with clinical features of Mitochondrial DNA Depletion Syndrome - TK2 Related (example, Garone_2018, Wang_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence suggesting disturbed ribonucleotide incorporation ratios in mitochondrial DNA in a patient cell line, however, does not allow clear conclusions about the variant effect (example, Berglund_2017). The following publications have been ascertained in the context of this evaluation (PMID: 28207748, 29602790, 29735374). ClinVar contains an entry for this variant (Variation ID: 38978). Based on the evidence outlined above, the variant was classified as pathogenic. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Benign

-0.060

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

D;.;D;.;.;D;.

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

D;D;.;D;D;D;D

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.89

D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Pathogenic

3.0

M;M;M;.;.;.;.

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-4.5

.;.;.;.;D;D;.

REVEL

Pathogenic

0.73

Sift

Pathogenic

0.0

.;.;.;.;D;D;.

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D

Polyphen

1.0

D;.;D;.;D;.;.

Vest4

0.91

MVP

0.99

MPC

1.0

ClinPred

0.94

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.87

gMVP

0.96

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over