Variant rs281865501 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM4_SupportingPP5_Very_Strong

The NM_004614.5(TK2):c.604_606del(p.Lys202del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0000217 in 1,614,174 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

TK2
NM_004614.5 inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4O:1

Conservation

PhyloP100: 5.87

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1

In a chain Thymidine kinase 2, mitochondrial (size 231) in uniprot entity KITM_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_004614.5

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_004614.5. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 16-66517147-CCTT-C is Pathogenic according to our data. Variant chr16-66517147-CCTT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 38995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TK2	NM_004614.5 linkuse as main transcript	c.604_606del	p.Lys202del	inframe_deletion	8/10	ENST00000544898.6	NP_004605.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TK2	ENST00000544898.6 linkuse as main transcript	c.604_606del	p.Lys202del	inframe_deletion	8/10	1	NM_004614.5	ENSP00000440898	P1	O00142-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251492

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1461850

Hom.:

AF XY:

0.0000220

AC XY:

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000225

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 18, 2023	This variant, c.604_606del, results in the deletion of 1 amino acid(s) of the TK2 protein (p.Lys202del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs281865501, gnomAD 0.003%). This variant has been observed in individual(s) with clinical features of mitochondrial myopathy (PMID: 12682338, 25948719, 29735374, 31060578). This variant is also known as K244Œî, K171del, and 730_732delAAG. ClinVar contains an entry for this variant (Variation ID: 38995). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 08, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of 1 amino acids in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19265691, 25948719, 12682338, 15571232, 20421844, 31060578, 30634555, 32161153, 31589614, 23230576, 29735374, 34973561) -

Mitochondrial DNA depletion syndrome, myopathic form

Pathogenic:1Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Dec 15, 2022	ACMG classification criteria: PM2 moderated, PM3 strong, PM4, PP1 supporting, PP4 -

Mitochondrial DNA depletion syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

May 11, 2022

Variant summary: TK2 c.604_606delAAG (p.Lys202del) results in an in-frame deletion that is predicted to remove one amino acid from the Deoxynucleoside kinase domain (IPR031314) of the encoded protein. The variant allele was found at a frequency of 4e-06 in 251492 control chromosomes. c.604_606delAAG has been reported in the literature as homozygous and compound heterozygous genotypes in individuals affected with Mitochondrial DNA Depletion Syndrome - TK2 Related (example, Vila_2003 cited in Villarroya_2009 and Frangini_2009, Camara_2015). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, Camara_2015). The most pronounced variant effect results in <10% of normal Thymidine kinase 2 (TK2) enzyme activity in fibroblasts from patients with a homozygous genotype. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over