TK2

thymidine kinase 2, the group of Deoxyribonucleoside kinases

Basic information

Region (hg38): 16:66508002-66552544

Links

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

Phenotypes

GenCC

Source: genCC

• mitochondrial DNA depletion syndrome, myopathic form (Definitive), 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 disease (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 (345 variants)
• Mitochondrial DNA depletion syndrome, myopathic form (115 variants)
• not specified (23 variants)
• Mitochondrial DNA depletion syndrome (15 variants)
• Inborn genetic diseases (11 variants)
• Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3 (5 variants)
• Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3;Mitochondrial DNA depletion syndrome, myopathic form (3 variants)
• Mitochondrial DNA depletion syndrome, myopathic form;Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3 (1 variants)
• Abnormality of the musculature (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.

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.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			3	52	1	56
missense	12	14	94	5	1	126
nonsense	5	1	2			8
start loss			2			2
frameshift	9	3				12
inframe indel		1	3			4
splice donor/acceptor (+/-2bp)		2				2
splice region		1	11	18	2	32
non coding		2	67	78	29	176
Total	26	23	171	135	31

Highest pathogenic variant AF is 0.000158

Variants in TK2

This is a list of pathogenic ClinVar variants found in the TK2 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
16-66508182-G-A		Mitochondrial DNA depletion syndrome, myopathic form	Benign (Jan 12, 2018)
16-66508205-C-A		Mitochondrial DNA depletion syndrome, myopathic form	Uncertain significance (Jan 13, 2018)
16-66508530-C-T		Mitochondrial DNA depletion syndrome, myopathic form	Uncertain significance (Jan 13, 2018)
16-66508600-C-A		Mitochondrial DNA depletion syndrome, myopathic form	Uncertain significance (Apr 27, 2017)
16-66508637-G-A		Mitochondrial DNA depletion syndrome, myopathic form	Uncertain significance (Jan 12, 2018)
16-66508683-C-T		Mitochondrial DNA depletion syndrome, myopathic form	Uncertain significance (Jan 12, 2018)
16-66508713-T-C		Mitochondrial DNA depletion syndrome, myopathic form	Uncertain significance (Jan 13, 2018)
16-66508750-T-G		Mitochondrial DNA depletion syndrome, myopathic form	Uncertain significance (Jan 12, 2018)
16-66508775-C-T		Mitochondrial DNA depletion syndrome, myopathic form	Uncertain significance (Jan 12, 2018)
16-66508983-C-T		Mitochondrial DNA depletion syndrome, myopathic form	Uncertain significance (Jan 13, 2018)
16-66509024-C-A		Mitochondrial DNA depletion syndrome, myopathic form	Uncertain significance (Jan 13, 2018)
16-66509054-G-A		Mitochondrial DNA depletion syndrome, myopathic form	Benign (Jan 13, 2018)
16-66509066-G-A		Mitochondrial DNA depletion syndrome, myopathic form	Uncertain significance (Jan 12, 2018)
16-66509195-G-C		Mitochondrial DNA depletion syndrome, myopathic form	Uncertain significance (Jan 13, 2018)
16-66509331-C-T		Mitochondrial DNA depletion syndrome, myopathic form	Uncertain significance (Jan 13, 2018)
16-66509428-C-A		Mitochondrial DNA depletion syndrome, myopathic form	Likely benign (Jan 13, 2018)
16-66509518-T-C		Mitochondrial DNA depletion syndrome, myopathic form	Benign (Jan 13, 2018)
16-66509535-T-C		Mitochondrial DNA depletion syndrome, myopathic form	Uncertain significance (Jan 13, 2018)
16-66509549-G-A		Mitochondrial DNA depletion syndrome, myopathic form	Benign (Jan 12, 2018)
16-66509593-C-T		Mitochondrial DNA depletion syndrome, myopathic form	Uncertain significance (Jan 13, 2018)
16-66509670-G-A		Mitochondrial DNA depletion syndrome, myopathic form	Likely benign (Jan 12, 2018)
16-66509747-A-G		Mitochondrial DNA depletion syndrome, myopathic form	Benign (Jan 13, 2018)
16-66509822-C-T		Mitochondrial DNA depletion syndrome, myopathic form	Uncertain significance (Jan 13, 2018)
16-66509846-C-T		Mitochondrial DNA depletion syndrome	Uncertain significance (Jun 14, 2016)
16-66509847-G-A		Mitochondrial DNA depletion syndrome, myopathic form	Uncertain significance (Jan 12, 2018)

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
3.91e-7	0.596	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

Haploinsufficiency Scores

• pHI: 0.179
• hipred: N
• hipred_score: 0.208
• ghis: 0.558

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

Mouse Genome Informatics

• Gene name: Tk2
• Phenotype: nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); liver/biliary system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); muscle phenotype; homeostasis/metabolism phenotype; cellular phenotype; growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan)

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