TDP2

tyrosyl-DNA phosphodiesterase 2

Basic information

Region (hg38): 6:24649979-24666930

Previous symbols: [ "TTRAP" ]

Links

ENSG00000111802 ∙ NCBI:51567 ∙ OMIM:605764 ∙ HGNC:17768 ∙ Uniprot:O95551 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• spinocerebellar ataxia, autosomal recessive 23 (Strong), mode of inheritance: AR
• spinocerebellar ataxia, autosomal recessive 23 (Supportive), mode of inheritance: AR
• spinocerebellar ataxia, autosomal recessive 23 (Strong), mode of inheritance: AR
• spinocerebellar ataxia, autosomal recessive 23 (Moderate), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Spinocerebellar ataxia, autosomal recessive 23	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	Neurologic	24658003

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TDP2 gene.

• Inborn_genetic_diseases (48 variants)
• not_provided (24 variants)
• Spinocerebellar_ataxia,_autosomal_recessive_23 (6 variants)
• TDP2-related_disorder (6 variants)
• Cerebellar_ataxia (1 variants)
• not_specified (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TDP2 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000016614.3. 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			1	9	1	11
missense			49	7	1	57
nonsense	5					5
start loss						0
frameshift	4	1				5
splice donor/acceptor (+/-2bp)	1	1				2
Total	10	2	50	16	2

Highest pathogenic variant AF is 0.0000841284

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TDP2	protein_coding	protein_coding	ENST00000378198	7	17057

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.13e-8	0.552	125693	0	55	125748	0.000219

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.115	183	187	0.976	0.00000886	2365
Missense in Polyphen		33	47.53	0.6943		598
Synonymous	-2.37	89	64.7	1.37	0.00000306	669
Loss of Function	1.10	15	20.4	0.737	0.00000125	229

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000336	0.000336
Ashkenazi Jewish	0.0000992	0.0000992
East Asian	0.000326	0.000326
Finnish	0.0000924	0.0000924
European (Non-Finnish)	0.000267	0.000264
Middle Eastern	0.000326	0.000326
South Asian	0.000229	0.000229
Other	0.000332	0.000326

dbNSFP

Source: dbNSFP

• Function: FUNCTION: DNA repair enzyme that can remove a variety of covalent adducts from DNA through hydrolysis of a 5'-phosphodiester bond, giving rise to DNA with a free 5' phosphate. Catalyzes the hydrolysis of dead-end complexes between DNA and the topoisomerase 2 (TOP2) active site tyrosine residue. The 5'-tyrosyl DNA phosphodiesterase activity can enable the repair of TOP2-induced DNA double-strand breaks/DSBs without the need for nuclease activity, creating a 'clean' DSB with 5'-phosphate termini that are ready for ligation. Thereby, protects the transcription of many genes involved in neurological development and maintenance from the abortive activity of TOP2. Hydrolyzes 5'- phosphoglycolates on protruding 5' ends on DSBs due to DNA damage by radiation and free radicals. Has preference for single-stranded DNA or duplex DNA with a 4 base pair overhang as substrate. Acts as a regulator of ribosome biogenesis following stress. Has also 3'-tyrosyl DNA phosphodiesterase activity, but less efficiently and much slower than TDP1. Constitutes the major if not only 5'- tyrosyl-DNA phosphodiesterase in cells. Also acts as an adapter by participating in the specific activation of MAP3K7/TAK1 in response to TGF-beta: associates with components of the TGF-beta receptor-TRAF6-TAK1 signaling module and promotes their ubiquitination dependent complex formation. Involved in non- canonical TGF-beta induced signaling routes. May also act as a negative regulator of ETS1 and may inhibit NF-kappa-B activation. {ECO:0000269|PubMed:19794497, ECO:0000269|PubMed:21030584, ECO:0000269|PubMed:21921940, ECO:0000269|PubMed:21980489, ECO:0000269|PubMed:22405347, ECO:0000269|PubMed:22822062, ECO:0000269|PubMed:24658003}.
• Disease: DISEASE: Spinocerebellar ataxia, autosomal recessive, 23 (SCAR23) [MIM:616949]: A form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCAR23 patients manifest epilepsy, intellectual disability, and gait ataxia. {ECO:0000269|PubMed:24658003}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Oxidative Damage;DNA Repair;Nonhomologous End-Joining (NHEJ);DNA Double-Strand Break Repair;CD40/CD40L signaling (Consensus)

Recessive Scores

• pRec: 0.122

Intolerance Scores

• rvis_EVS: 1.04
• rvis_percentile_EVS: 91.26

Haploinsufficiency Scores

• pHI: 0.826
• hipred: N
• hipred_score: 0.380
• ghis: 0.410

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: H
• gene_indispensability_pred: E
• gene_indispensability_score: 0.824

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Tdp2
• Phenotype: hematopoietic system phenotype; normal phenotype; immune system phenotype; digestive/alimentary phenotype; growth/size/body region phenotype; endocrine/exocrine gland phenotype; homeostasis/metabolism phenotype; cellular phenotype

Zebrafish Information Network

• Gene name: tdp2b
• Affected structure: head
• Phenotype tag: abnormal
• Phenotype quality: decreased size

Gene ontology

• Biological process: double-strand break repair;cell surface receptor signaling pathway;neuron development;nucleic acid phosphodiester bond hydrolysis;negative regulation of nucleic acid-templated transcription
• Cellular component: nucleus;nucleoplasm;nucleolus;cytoplasm;aggresome;nuclear body;PML body
• Molecular function: magnesium ion binding;single-stranded DNA binding;transcription corepressor activity;nuclease activity;protein binding;manganese ion binding;tyrosyl-RNA phosphodiesterase activity;5'-tyrosyl-DNA phosphodiesterase activity