TK2

thymidine kinase 2, the group of Deoxyribonucleoside kinases

Basic information

Region (hg38): 16:66508003-66552544

Links

ENSG00000166548 ∙ NCBI:7084 ∙ OMIM:188250 ∙ HGNC:11831 ∙ Uniprot:O00142 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• mitochondrial disease (Definitive), mode of inheritance: AR
• mitochondrial DNA depletion syndrome, myopathic form (Strong), mode of inheritance: AR
• mitochondrial DNA depletion syndrome, myopathic form (Supportive), mode of inheritance: AR
• autosomal recessive progressive external ophthalmoplegia (Supportive), mode of inheritance: AR
• mitochondrial DNA depletion syndrome, myopathic form (Strong), mode of inheritance: AR
• mitochondrial DNA depletion syndrome, myopathic form (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Mitochondrial DNA depletion syndrome 2; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3	AR	General	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	Biochemical; Musculoskeletal	1734306; 11687801; 12391347; 18819985; 19125351; 19736010; 19815440; 20421844; 21937588; 22345218

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TK2 gene.

• not_provided (442 variants)
• Mitochondrial_disease (101 variants)
• Mitochondrial_DNA_depletion_syndrome,_myopathic_form (65 variants)
• not_specified (34 variants)
• Inborn_genetic_diseases (29 variants)
• Progressive_external_ophthalmoplegia_with_mitochondrial_DNA_deletions,_autosomal_recessive_3 (22 variants)
• Mitochondrial_DNA_depletion_syndrome (16 variants)
• TK2-related_disorder (14 variants)
• Abnormality_of_the_musculature (1 variants)
• Mitochondrial_DNA_depletion_syndrome_2,_myopathic_form (1 variants)
• Inborn_mitochondrial_myopathy (1 variants)
• Myopathy (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TK2 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000004614.5. Only rare variants are included in the table.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			7	103	1	111
missense	10	52	123	8	1	194
nonsense	9	2				11
start loss	2					2
frameshift	22	5				27
splice donor/acceptor (+/-2bp)	3	7	6			16
Total	46	66	136	111	2

Highest pathogenic variant AF is 0.00008487797

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TK2	protein_coding	protein_coding	ENST00000451102	10	44542

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
		125719	0	29	125748	0.000115

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.153	139	144	0.964	0.00000860	1716
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000210	0.000210
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.000132	0.000132
Middle Eastern	0.00	0.00
South Asian	0.000261	0.000261
Other	0.00	0.00

dbNSFP

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.
• Pathway: Pyrimidine metabolism - Homo sapiens (human);Drug metabolism - other enzymes - Homo sapiens (human);Pyrimidine metabolism;Metabolism of nucleotides;Metabolism;Pyrimidine salvage;Nucleotide salvage;Pyrimidine metabolism;superpathway of pyrimidine deoxyribonucleoside salvage;Pyrimidine nucleotides nucleosides metabolism;pyrimidine deoxyribonucleosides salvage (Consensus)

Recessive Scores

• pRec: 0.649

Intolerance Scores

• loftool: 0.139
• rvis_EVS: -0.25
• rvis_percentile_EVS: 35.42

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.574

Gene Damage Prediction

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

Gene ontology

• Biological process: nucleobase-containing compound metabolic process;deoxyribonucleoside monophosphate biosynthetic process;nucleotide biosynthetic process;phosphorylation;pyrimidine nucleoside salvage;deoxycytidine metabolic process;thymidine metabolic process;DNA biosynthetic process
• Cellular component: cytoplasm;mitochondrion;mitochondrial matrix
• Molecular function: deoxycytidine kinase activity;thymidine kinase activity;ATP binding;deoxynucleoside kinase activity;nucleoside kinase activity