TK2

protein-coding

thymidine kinase 2, the group of Deoxyribonucleoside kinases

Gene summary

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]

MANE transcript

NM_004614.5

Inheritance

ClinVar variants

P:110U:145B:121

Top phenotype

Mitochondrial DNA depletion syndrome 2; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3

gnomAD constraint

pLI —, LoF o/e 0.73

Max pathogenic AF

—

Genomic locus

chr16:66,508,003-66,552,544

External References & Databases

Ensembl (ENSG00000166548)

Transcript & Mutation Effects

hg38 • Region Span ~44.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial DNA depletion syndrome, myopathic formDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012301

Submitter: G2P

autosomal recessive progressive external ophthalmoplegiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016810

Submitter: Orphanet

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *TK2* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of September 6, 2023. The *TK2* gene encodes mitochondrial thymidine kinase 2, a mitochondrial deoxyribonucleoside kinase that phosphorylates thymidine, deoxycytidine, and deoxyuridine. Defects of this protein lead to impaired synthesis of mtDNA precursors leading to mtDNA depletion. The *TK2* gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2001 (PMID 11687801), in individuals with infantile onset severe myopathy. While various names have been given to the constellation of features seen in those with *TK2*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *TK2* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 11 unique variants (six missense, two frameshift, three stop-gained variants) from three publications (PMIDs: 11687801, 16908738, 29602790) although there are over 100 cases reported in the medical literature. Age of onset varies from infancy to adulthood and outcomes range from death in infancy to being alive in adulthood at the time of report. Features seen in affected individuals include myopathy (muscle weakness that leads to respiratory failure in some), seizures, dysarthria, dysphagia, respiratory insufficiency, ophthalmoplegia, and sensorineural hearing loss. Muscle biopsies show mitochondrial DNA depletion and combined mitochondrial respiratory chain enzyme deficiencies. The mechanism of disease appears to be loss of function. This gene-disease relationship is also supported by its known biochemical function, knockout mouse model, and knock-in mouse model with a variant found in a patient showing ataxic, progressive muscle weakness and TK2 deficiency phenotype (PMIDs: 33340416, 15639197, 18467430, 20123860). In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed since the first proposal of the association. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. No convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on September 6, 2023 (SOP Version 9).

mitochondrial DNA depletion syndrome, myopathic formSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012301

Submitter: PanelApp Australia

mitochondrial DNA depletion syndrome, myopathic formSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012301

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Mitochondrial DNA depletion syndrome 2; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3AR

Manifestation: Biochemical; Musculoskeletal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 1734306; 11687801; 12391347; 18819985; 19125351; 19736010; 19815440; 20421844; 21937588; 22345218

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TK2 variants in ClinVar

14 Conditions Cataloged

not providedTotal: 460

Mitochondrial diseaseTotal: 101

Mitochondrial DNA depletion syndrome, myopathic formTotal: 67

not specifiedTotal: 46

Inborn genetic diseasesTotal: 29

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3Total: 24

TK2-related disorderTotal: 23

Mitochondrial DNA depletion syndromeTotal: 16

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004614.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			6 clinvar	112 clinvar		118
missense	8 clinvar	52 clinvar	133 clinvar	8 clinvar	1 clinvar	202
nonsense	9 clinvar	2 clinvar				11
start loss	2 clinvar					2
frameshift	22 clinvar	5 clinvar				27
splice donor/acceptor (+/-2bp)	3 clinvar	7 clinvar	6 clinvar			16
Total	44	66	145	120	1	376

Highest pathogenic variant AF is 0.00008487797

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 62 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004614.5	RefSeq	NP_004605.4	10	MANE Select
ENST00000544898.6	Ensembl	ENSP00000440898.2	10	MANE Select
NM_001172643.1	RefSeq	NP_001166114.1	10	Standard
NM_001172644.2	RefSeq	NP_001166115.1	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Pyrimidine metabolism - Homo sapiens (human)
Drug metabolism - other enzymes - Homo sapiens (human)
Pyrimidine metabolism
Metabolism of nucleotides
Metabolism

Biological Process

nucleobase-containing compound metabolic process
deoxyribonucleoside monophosphate biosynthetic process
nucleotide biosynthetic process
phosphorylation
pyrimidine nucleoside salvage

Molecular Function

deoxycytidine kinase activity
thymidine kinase activity
ATP binding
deoxynucleoside kinase activity
nucleoside kinase activity

Cellular Component

cytoplasm
mitochondrion
mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000451102
Coding exons: 10
Length: 44542
Individuals with no LoFs: 125719
Homozygous LoFs: 0
Heterozygous LoFs: 29
Defined: 125748
p: 0.000115

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.153	139	144	0.964	0.00000860	1716
Missense (PolyPhen)		45	54.178	0.83059		652
Synonymous	-0.890	64	55.6	1.15	0.00000366	490
Loss of Function	1.01	12	16.4	0.732	7.24e-7	202

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00013	0.00013	rare
South Asian	0.00026	0.00026	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Phosphorylates thymidine, deoxycytidine, and deoxyuridine in the mitochondrial matrix. In non-replicating cells, where cytosolic dNTP synthesis is down-regulated, mtDNA synthesis depends solely on TK2 and DGUOK. Widely used as target of antiviral and chemotherapeutic agents. {ECO:0000269|PubMed:11687801}.;
Disease: DISEASE: Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3 (PEOB3) [MIM:617069]: A form of progressive external ophthalmoplegia, a mitochondrial myopathy characterized by progressive paralysis of the levator palpebrae, orbicularis oculi, and extraocular muscles. PEOB3 patients manifest adult-onset progressive external ophthalmoplegia and progressive proximal muscle weakness associated with muscle atrophy. {ECO:0000269|PubMed:21937588}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.649

Intolerance Scores

LoFtool: 0.139
RVIS EVS: -0.25
RVIS percentile EVS: 35.42

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.574

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium