TOP2A
protein-codingDNA topoisomerase II alpha, the group of Topoisomerases
Gene summary
This gene encodes a DNA topoisomerase, an enzyme that controls and alters the topologic states of DNA during transcription. This nuclear enzyme is involved in processes such as chromosome condensation, chromatid separation, and the relief of torsional stress that occurs during DNA transcription and replication. It catalyzes the transient breaking and rejoining of two strands of duplex DNA which allows the strands to pass through one another, thus altering the topology of DNA. Two forms of this enzyme exist as likely products of a gene duplication event. The gene encoding this form, alpha, is localized to chromosome 17 and the beta gene is localized to chromosome 3. The gene encoding this enzyme functions as the target for several anticancer agents and a variety of mutations in this gene have been associated with the development of drug resistance. Reduced activity of this enzyme may also play a role in ataxia-telangiectasia. [provided by RefSeq, Jul 2010]
- TOP2
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~29.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
No GenCC data available for this gene.
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to TOP2A variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001067.4. 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 | 2 | 7 | 6 | 15 | ||
| missense | 113 | 12 | 2 | 127 | ||
| nonsense | 3 | 3 | ||||
| start loss | 0 | |||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 4 | 4 | ||||
| Total | 0 | 0 | 123 | 19 | 8 | 150 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001058.2 | 35 | MANE Select | |
| Ensembl | ENSP00000411532.1 | 35 | MANE Select | |
| Ensembl | ENSP00000464055.1 | 1 | Standard | |
| Ensembl | ENSP00000462908.1 | 4 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| top2a | Danio rerio | Structure: neural tube Quality: apoptotic abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Doxorubicin Pathway (Cancer Cell), Pharmacodynamics
- Etoposide Pathway, Pharmacokinetics/Pharmacodynamics
- Etoposide Action Pathway
- Teniposide Action Pathway
- Teniposide Metabolism Pathway
Biological Process
- resolution of meiotic recombination intermediates
- sister chromatid segregation
- hematopoietic progenitor cell differentiation
- DNA topological change
- DNA ligation
Molecular Function
- magnesium ion binding
- DNA binding
- chromatin binding
- RNA binding
- DNA topoisomerase type II (ATP-hydrolyzing) activity
Cellular Component
- nuclear chromosome
- condensed chromosome
- nucleus
- nucleoplasm
- nucleolus
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000423485
- Coding exons
- 35
- Length
- 29435
- Individuals with no LoFs
- 124609
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 45
- Defined
- 124654
- p
- 0.000181
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 4.04 | 448 | 762 | 0.588 | 0.0000378 | 10175 |
| Missense (PolyPhen) | 84 | 275.11 | 0.30534 | 3647 | ||
| Synonymous | 1.70 | 221 | 256 | 0.865 | 0.0000126 | 2692 |
| Loss of Function | 6.75 | 15 | 80.2 | 0.187 | 0.00000437 | 1057 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00047 | 0.00045 | rare |
| Latino/Admixed American | 0.000088 | 0.000087 | rare |
| Ashkenazi Jewish | 0.00010 | 0.000099 | rare |
| East Asian | 0.000062 | 0.000056 | rare |
| Finnish | 0.000047 | 0.000046 | rare |
| European (Non-Finnish) | 0.00020 | 0.00019 | rare |
| South Asian | 0.00034 | 0.00029 | rare |
| Other | 0.00017 | 0.00017 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Control of topological states of DNA by transient breakage and subsequent rejoining of DNA strands. Topoisomerase II makes double-strand breaks. Essential during mitosis and meiosis for proper segregation of daughter chromosomes. May play a role in regulating the period length of ARNTL/BMAL1 transcriptional oscillation (By similarity). {ECO:0000250|UniProtKB:Q01320, ECO:0000269|PubMed:18790802, ECO:0000269|PubMed:22013166, ECO:0000269|PubMed:22323612}.;
Recessive Scores
- pRec
- 0.545
Intolerance Scores
- LoFtool
- 0.689
- RVIS EVS
- 0.49
- RVIS percentile EVS
- 79.61
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.960
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |