Genetic Variant NM_004614.5:c.94C>T (chr16-66549968-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004614.5(TK2):c.94C>T(p.Arg32Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00703 in 1,461,434 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R32Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0061 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0071 ( 50 hom. )

Consequence

TK2
NM_004614.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.04

Publications

5 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:

ENSG00000261519 (HGNC:):

ENSG00000261519 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0023220778).

BP6

Variant 16-66549968-G-A is Benign according to our data. Variant chr16-66549968-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 215261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00614 (934/152238) while in subpopulation NFE AF = 0.00785 (534/67986). AF 95% confidence interval is 0.0073. There are 4 homozygotes in GnomAd4. There are 496 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

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.94C>T	p.Arg32Trp	missense	Exon 1 of 10	NP_004605.4
TK2	NM_001172645.2		c.94C>T	p.Arg32Trp	missense	Exon 1 of 9	NP_001166116.1	O00142-4
TK2	NM_001172644.2		c.94C>T	p.Arg32Trp	missense	Exon 1 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.94C>T	p.Arg32Trp	missense	Exon 1 of 10	ENSP00000440898.2	O00142-1
TK2	ENST00000527284.6	TSL:1	c.37C>T	p.Arg13Trp	missense	Exon 1 of 9	ENSP00000435312.2	A0A7P0PE46
TK2	ENST00000451102.7	TSL:1	c.31+285C>T		intron	N/A	ENSP00000414334.4	O00142-2

Frequencies

GnomAD3 genomes

AF:

0.00614

AC:

934

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00128

Gnomad AMI

AF:

0.0275

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.0258

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00785

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.00727

AC:

483

AN:

66464

AF XY:

0.00665

show subpopulations

Gnomad AFR exome

AF:

0.00280

Gnomad AMR exome

AF:

0.00163

Gnomad ASJ exome

AF:

0.00139

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0238

Gnomad NFE exome

AF:

0.00983

Gnomad OTH exome

AF:

0.00542

GnomAD4 exome

AF:

0.00713

AC:

9333

AN:

1309196

Hom.:

Cov.:

AF XY:

0.00694

AC XY:

4467

AN XY:

643454

show subpopulations

African (AFR)

AF:

0.00144

AC:

AN:

25708

American (AMR)

AF:

0.00164

AC:

AN:

21340

Ashkenazi Jewish (ASJ)

AF:

0.000803

AC:

AN:

19928

East Asian (EAS)

AF:

0.00

AC:

AN:

31940

South Asian (SAS)

AF:

0.00305

AC:

203

AN:

66576

European-Finnish (FIN)

AF:

0.0248

AC:

901

AN:

36376

Middle Eastern (MID)

AF:

0.00184

AC:

AN:

3804

European-Non Finnish (NFE)

AF:

0.00748

AC:

7850

AN:

1049342

Other (OTH)

AF:

0.00524

AC:

284

AN:

54182

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

570

1139

1709

2278

2848

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

296

592

888

1184

1480

<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:

0.00614

AC:

934

AN:

152238

Hom.:

Cov.:

AF XY:

0.00666

AC XY:

496

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.00128

AC:

AN:

41566

American (AMR)

AF:

0.00137

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0258

AC:

274

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00785

AC:

534

AN:

67986

Other (OTH)

AF:

0.00190

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

106

160

213

266

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00652

Hom.:

Bravo

AF:

0.00391

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00571

AC:

ExAC

AF:

0.00386

AC:

327

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (2)

Mitochondrial disease (1)

Mitochondrial DNA depletion syndrome, myopathic form (1)

TK2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

0.010

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.72

MetaRNN

Benign

0.0023

MetaSVM

Uncertain

0.64

MutationAssessor

Benign

0.69

PhyloP100

2.0

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.73

REVEL

Uncertain

0.36

Sift

Benign

0.041

Sift4G

Uncertain

0.038

Polyphen

0.99

Vest4

0.17

MVP

0.98

MPC

0.37

ClinPred

0.057

GERP RS

1.8

PromoterAI

-0.067

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.091

gMVP

0.42

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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