Genetic Variant TK2:p.Thr108Met (chr16-66531432-G-A) – ACMG Classification: Pathogenic (15 pts)

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3PM1PP3PP5_Very_Strong

The NM_004614.5(TK2):c.323C>T(p.Thr108Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000378 in 1,614,060 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 (★★). ClinVar reports functional evidence for this variant: "SCV000538066: Functional studies have shown this variant reduces protein expression, enzymatic activity, and catalytic efficiency of TK2 (Mancuso et al., 2002" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T108A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

TK2
NM_004614.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:15O:1

Conservation

PhyloP100: 5.48

Publications

33 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: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae), G2P
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 15 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000538066: Functional studies have shown this variant reduces protein expression, enzymatic activity, and catalytic efficiency of TK2 (Mancuso et al., 2002; Wang et al., 2005; Villarroya et al., 2009).; SCV001423758: Wang et al. (2005) demonstrated that the p.Thr108Met variant enzyme had approximately 3-4% of the activity and approximately 0.5% of the efficiency of the wild type enzyme. Modeling of the TK2 enzyme showed that the Thr108 residue lies in helix four and is involved in active site formation, and an alteration at this residue could disrupt hydrogen bonding (Wang et al. 2005).; SCV002058407: "Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product." PMID:15639197; SCV004231894: Functional studies described in the literature (PMID: 15639197).; SCV005042560: Functional studies have shown this variant reduces protein expression, enzymatic activity, and catalytic efficiency of TK2 Wang et al., 2005; Mancuso et al., 2003.; SCV000252384: Published functional studies found this variant is associated with a significant decrease in enzyme efficiency and catalytic activity compared to wild-type (PMID: 15639197);; SCV001414868: Experimental studies have shown that this missense change affects TK2 function (PMID: 12391347, 12873860, 15639197, 19265691, 24484525, 28812460).; SCV004814035: "At least one publication reports experimental evidence evaluating an impact on protein function (Wang_2005). The most pronounced variant effect results in <10% of enzyme activity versus the WT protein." PMID: 25948719; SCV005344697: This particular substitution has been shown to lead to an approximately 100-fold decrease in the enzyme efficiency of thymidine kinase 2 (TK2) (defined as “T77M” in Wang et al. 2005. PubMed ID: 15639197).; SCV005911759: Experimental studies have shown that this variant results in a significant reduction of catalytic activity compared to the wild type. PMID:15639197

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_004614.5

PP3

MetaRNN computational evidence supports a deleterious effect, 0.8

PP5

Variant 16-66531432-G-A is Pathogenic according to our data. Variant chr16-66531432-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 12710.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004614.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TK2	NM_004614.5	MANE Select	c.323C>T	p.Thr108Met	missense	Exon 5 of 10	NP_004605.4
TK2	NM_001172645.2		c.269C>T	p.Thr90Met	missense	Exon 4 of 9	NP_001166116.1	O00142-4
TK2	NM_001172644.2		c.248C>T	p.Thr83Met	missense	Exon 4 of 9	NP_001166115.1	O00142-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TK2	ENST00000544898.6	TSL:1 MANE Select	c.323C>T	p.Thr108Met	missense	Exon 5 of 10	ENSP00000440898.2	O00142-1
TK2	ENST00000451102.7	TSL:1	c.230C>T	p.Thr77Met	missense	Exon 5 of 10	ENSP00000414334.4	O00142-2
TK2	ENST00000527284.6	TSL:1	c.266C>T	p.Thr89Met	missense	Exon 5 of 9	ENSP00000435312.2	A0A7P0PE46

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000438

AC:

AN:

251080

AF XY:

0.0000663

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000287

AC:

AN:

1461870

Hom.:

Cov.:

AF XY:

0.0000399

AC XY:

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33480

American (AMR)

AF:

0.000268

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000162

AC:

AN:

1112002

Other (OTH)

AF:

0.0000994

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.000125

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41450

American (AMR)

AF:

0.00105

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000197

Hom.:

Bravo

AF:

0.000234

ExAC

AF:

0.0000247

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Mitochondrial DNA depletion syndrome, myopathic form (8)

not provided (3)

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3 (2)

Mitochondrial disease (1)

Mitochondrial DNA depletion syndrome (1)

TK2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.96

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.50

MetaRNN

Pathogenic

0.80

MetaSVM

Pathogenic

0.86

MutationAssessor

Pathogenic

3.0

PhyloP100

5.5

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-3.7

REVEL

Pathogenic

0.85

Sift

Benign

0.063

Sift4G

Uncertain

0.028

Polyphen

1.0

Vest4

0.84

MVP

0.96

MPC

1.1

ClinPred

0.61

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.47

gMVP

0.83

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over