16-66531394-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS1_Very_StrongPM1PM5PP5_Very_Strong

The NM_004614.5(TK2):c.361C>A(p.His121Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000452 in 1,614,186 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H121D) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

TK2
NM_004614.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 5.48

Publications

32 publications found

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 Gene-Disease associations (from GenCC):

mitochondrial disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
mitochondrial DNA depletion syndrome, myopathic form
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
autosomal recessive progressive external ophthalmoplegia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TK2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 20 ACMG points.

PS1

Transcript NM_004614.5 (TK2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_004614.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-66531394-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3778845.Status of the report is criteria_provided_single_submitter, 1 stars.

PP5

Variant 16-66531394-G-T is Pathogenic according to our data. Variant chr16-66531394-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 12708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TK2	NM_004614.5 link	c.361C>A	p.His121Asn	missense_variant	Exon 5 of 10	ENST00000544898.6	NP_004605.4	O00142-1Q8IZR3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TK2	ENST00000544898.6 link	c.361C>A	p.His121Asn	missense_variant	Exon 5 of 10	1	NM_004614.5	ENSP00000440898.2		O00142-1

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.000576

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

GnomAD2 exomes

AF:

0.000116

AC:

AN:

250912

AF XY:

0.000125

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000434

Gnomad ASJ exome

AF:

0.000893

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000442

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000335

AC:

AN:

1461852

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.000402

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000612

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000809

AC:

AN:

1111980

Other (OTH)

AF:

0.0000994

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.443

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000158

AC:

AN:

152334

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41574

American (AMR)

AF:

0.00144

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000381

Hom.:

Bravo

AF:

0.0000756

ExAC

AF:

0.0000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mitochondrial DNA depletion syndrome, myopathic form

Pathogenic:2

Feb 28, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Sep 01, 2017

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has been previously reported as disease-causing and was found twice our laboratory: homozygous in a 4-year-old male with developmental regression, progressive muscle weakness, hypotonia, flat feet, Gower sign, arachnoid cyst; in trans with another pathogenic variant (R183W) in a 16-year-old female with proximal muscle weakness. Heterozygotes are expected to be asymptomatic carriers. -

Mitochondrial disease

Pathogenic:1

Apr 10, 2025

Genomenon, Inc, Genomenon, Inc

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

TK2 His121Asn (c.361C>A) is a missense variant that changes the amino acid at residue 121 from Histidine to Asparagine. It is also described as H163N, His90Asn, and H90N in the literature. This variant has been observed in multiple probands affected with mitochondrial disease in both the homozygous and compound heterozygous state (PMID:29735374;38544965). Experimental studies have shown that this variant results in a significant reduction in catalytic activity as compared to wild type (PMID:12493767). This variant is not present at a significant frequency in gnomAD, and in silico models agree that this variant is possibly or probably damaging. In conclusion, we classify TK2 His121Asn (c.361C>A) as a pathogenic variant. -

Mitochondrial DNA depletion syndrome

Pathogenic:1

Mar 21, 2024

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TK2 c.361C>A (p.His121Asn) 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 0.00012 in 250912 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TK2 causing Mitochondrial DNA Depletion Syndrome - TK2 Related (0.00012 vs 0.0011), allowing no conclusion about variant significance. c.361C>A has been reported in the literature in multiple individuals affected with Mitochondrial DNA Depletion Syndrome (example, Chanprasert_2013, Mancuso_2002). These data indicate that the variant is very 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: 23932787, 12873860). ClinVar contains an entry for this variant (Variation ID: 12708). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1

Aug 12, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Benign

-0.024

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.97

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

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

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

M_CAP

Pathogenic

0.61

MetaRNN

Uncertain

0.67

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.9

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

PhyloP100

5.5

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-5.6

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

REVEL

Pathogenic

0.69

Sift

Uncertain

0.025

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

Sift4G

Uncertain

0.0070

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

Polyphen

1.0

D;.;D;.;.;P;.;.;.;.;.;.;.

Vest4

0.71

MVP

0.99

MPC

1.2

ClinPred

0.89

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.86

gMVP

0.92

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

1.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over