rs281865489

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2PP5BP4

The ENST00000527800.6(TK2):c.-24C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.00000867 in 1,613,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

TK2
ENST00000527800.6 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1

Conservation

PhyloP100: 3.67

Publications

7 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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-66536981-G-A is Pathogenic according to our data. Variant chr16-66536981-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 38982.

BP4

Computational evidence support a benign effect (MetaRNN=0.2419571). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000527800.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TK2	NM_004614.5	MANE Select	c.268C>T	p.Arg90Cys	missense	Exon 4 of 10	NP_004605.4
TK2	NM_001272050.2		c.-24C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 10	NP_001258979.1
TK2	NM_001172644.2		c.193C>T	p.Arg65Cys	missense	Exon 3 of 9	NP_001166115.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TK2	ENST00000527800.6	TSL:1	c.-24C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 9	ENSP00000433770.1
TK2	ENST00000544898.6	TSL:1 MANE Select	c.268C>T	p.Arg90Cys	missense	Exon 4 of 10	ENSP00000440898.2
TK2	ENST00000451102.7	TSL:1	c.175C>T	p.Arg59Cys	missense	Exon 4 of 10	ENSP00000414334.4

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152002

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000945

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

251486

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000131

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

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:

0.00000658

AC:

AN:

152002

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74234

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41392

American (AMR)

AF:

0.00

AC:

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0000945

AC:

AN:

10578

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67994

Other (OTH)

AF:

0.00

AC:

AN:

2088

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

Alfa

AF:

0.0000154

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Mitochondrial disease (1)

Mitochondrial DNA depletion syndrome, myopathic form (1)

Myopathy (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.89

Eigen

Benign

-0.070

Eigen_PC

Benign

0.085

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.047

MetaRNN

Benign

0.24

MetaSVM

Uncertain

0.031

MutationAssessor

Benign

1.8

PhyloP100

3.7

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-3.5

REVEL

Uncertain

0.60

Sift

Benign

0.13

Sift4G

Benign

0.12

Polyphen

0.023

Vest4

0.30

MutPred

0.56

Loss of MoRF binding (P = 0.0355)

MVP

0.98

MPC

0.49

ClinPred

0.88

GERP RS

4.3

PromoterAI

-0.037

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.13

gMVP

0.69

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over