chr16-66517147-CCTT-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1PM2PM4_SupportingPP5_Very_Strong

The NM_004614.5(TK2):c.604_606delAAG(p.Lys202del) variant causes a conservative 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 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6O:1

Conservation

PhyloP100: 5.87

Publications

10 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:

ENSG00000260851 (HGNC:):

ENSG00000260851 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 38995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TK2	NM_004614.5 link	c.604_606delAAG	p.Lys202del	conservative_inframe_deletion	Exon 8 of 10	ENST00000544898.6	NP_004605.4	O00142-1Q8IZR3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TK2	ENST00000544898.6 link	c.604_606delAAG	p.Lys202del	conservative_inframe_deletion	Exon 8 of 10	1	NM_004614.5	ENSP00000440898.2		O00142-1
ENSG00000260851	ENST00000561728.1 link	n.52_54delAAG		non_coding_transcript_exon_variant	Exon 1 of 6	2		ENSP00000462196.1		J3KRW8

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

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251492

AF XY:

0.00

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 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

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000671

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000225

AC:

AN:

1111982

Other (OTH)

AF:

0.0000331

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.422

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:

0.0000328

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41556

American (AMR)

AF:

0.0000653

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.555

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Jan 05, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Dec 08, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Dec 15, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PM2 moderated, PM3 strong, PM4, PP1 supporting, PP4 -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Inborn genetic diseases

Pathogenic:1

Jul 12, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.604_606delAAG (p.K202del) alteration is located in exon 8 (coding exon 8) of the TK2 gene. This alteration consists of an in-frame deletion of 3 nucleotides between nucleotide positions c.604 and c.606, resulting in the deletion of a lysine (K) residue at codon 202. Based on data from gnomAD, the c.604_606delAAG allele has an overall frequency of <0.001% (1/251492) total alleles studied. The highest observed frequency was 0.003% (1/34592) of Latino alleles. This variant has been identified in the homozygous state and/or in conjunction with other TK2 variants in individuals with features consistent withTK2-related mitochondrial DNA depletion syndrome (Ceballos, 2024; Morganroth, 2023; Jou, 2019; Domínguez-González, 2019; Wang, 2018). This amino acid position is not well conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis (Choi, 2012). Based on the available evidence, this alteration is classified as pathogenic. -

Mitochondrial disease

Pathogenic:1

Apr 10, 2025

Genomenon, Inc, Genomenon, Inc

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

TK2 p.Lys202del (c.604_606del) is an in-frame deletion variant that causes the removal of a single Lysine at residue 202. It is also described as K244del and K171del in the literature. This variant has been observed in multiple probands affected with mitochondrial disease in both the homozygous and compound heterozygous state (PMID:34973561;35286480;20421844;29735374;31060578). TK2 K202del was found to segregate with disease in multiple affected families (PMID:29735374;31060578). Experimental studies showed reduced activity, however, the significance of this finding remains unclear (PMID:19154348). This variant is not present at a significant frequency in gnomAD. In conclusion, we classify TK2 p.Lys202del (c.604_606del) as a pathogenic variant. -

Mitochondrial DNA depletion syndrome

Pathogenic:1

May 11, 2022

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

PhyloP100

5.9

Mutation Taster

=78/22

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over