dbSNP rs725131: TK2:c.-351-89G>C (chr16-66551807-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000569718.6(TK2):c.-351-89G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.249 in 152,150 control chromosomes in the GnomAD database, including 7,212 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.25 ( 7212 hom., cov: 33)

Exomes 𝑓: 0.12 ( 0 hom. )

Consequence

TK2
ENST00000569718.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.275

Publications

15 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: G2P, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia
autosomal recessive progressive external ophthalmoplegia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TK2 links:

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new If you want to explore the variant's impact on the transcript ENST00000569718.6, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.52 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000569718.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TK2	ENST00000569718.6	TSL:1	c.-351-89G>C	intron	N/A	ENSP00000464313.2	J3QRP0
TK2	ENST00000678015.1		c.-563G>C	5_prime_UTR	Exon 1 of 10	ENSP00000502959.1	O00142-5
TK2	ENST00000678297.1		c.-488G>C	5_prime_UTR	Exon 1 of 9	ENSP00000503472.1	O00142-5

Frequencies

GnomAD3 genomes

AF:

0.249

AC:

37886

AN:

151998

Hom.:

7192

Cov.:

show subpopulations

Gnomad AFR

AF:

0.525

Gnomad AMI

AF:

0.169

Gnomad AMR

AF:

0.248

Gnomad ASJ

AF:

0.110

Gnomad EAS

AF:

0.293

Gnomad SAS

AF:

0.218

Gnomad FIN

AF:

0.0962

Gnomad MID

AF:

0.127

Gnomad NFE

AF:

0.115

Gnomad OTH

AF:

0.208

GnomAD4 exome

AF:

0.118

AC:

AN:

Hom.:

AF XY:

0.0625

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.182

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.250

AC:

37957

AN:

152116

Hom.:

7212

Cov.:

AF XY:

0.248

AC XY:

18413

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.525

AC:

21781

AN:

41460

American (AMR)

AF:

0.248

AC:

3789

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.110

AC:

382

AN:

3472

East Asian (EAS)

AF:

0.293

AC:

1514

AN:

5176

South Asian (SAS)

AF:

0.218

AC:

1049

AN:

4818

European-Finnish (FIN)

AF:

0.0962

AC:

1020

AN:

10602

Middle Eastern (MID)

AF:

0.134

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.115

AC:

7791

AN:

67998

Other (OTH)

AF:

0.207

AC:

438

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1238

2476

3715

4953

6191

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

350

700

1050

1400

1750

<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:

0.185

Hom.:

570

Bravo

AF:

0.276

Asia WGS

AF:

0.271

AC:

941

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

5.5

(source)

DANN

Benign

0.56

PhyloP100

0.28

PromoterAI

0.017

Neutral

(source)

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over