TOP2B

Chr 3AD

DNA topoisomerase II beta

Also known as: BILU, TOPIIB, top2beta

NCBI Gene: 7155ENSG00000077097UniProt: Q02880OMIM: 126431

This gene encodes DNA topoisomerase II beta, which alters DNA topology by creating transient double-strand breaks to allow DNA strands to pass through each other during transcription and replication, and specifically functions as a key decatenating enzyme important for B-cell differentiation. Mutations cause autosomal dominant B-cell immunodeficiency with distal limb anomalies and urogenital malformations. The gene is highly constrained against loss-of-function variants, indicating that such mutations are likely to be severely deleterious.

OMIMResearchSummary from RefSeq, OMIM, UniProt
MultiplemechanismADLOEUF 0.251 OMIM phenotype
Clinical Summary— TOP2B
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Gene-Disease Validity (ClinGen)
B-cell immunodeficiency, distal limb anomalies, and urogenital malformations · ADModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
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ClinVar Variants
4 unique Pathogenic / Likely Pathogenic· 282 VUS of 600 total submissions
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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint
0.25LOEUF
pLI 1.000
Z-score 6.97
OE 0.15 (0.10–0.25)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint
3.86Z-score
OE missense 0.61 (0.56–0.66)
474 obs / 777.1 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios
LoF OE0.15 (0.10–0.25)
0≤0.351.4
Missense OE0.61 (0.56–0.66)
0≤0.61.4
Synonymous OE0.93
0≤1.21.6
LoF obs/exp: 12 / 78.8Missense obs/exp: 474 / 777.1Syn Z: 0.86
DN
0.3991th %ile
GOF
0.2995th %ile
LOF
0.67top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · LOEUF 0.25
DN1 literature citation

Literature Evidence

DNWe use Saccharomyces cerevisiae, and knockin and knockout murine models, to demonstrate that patient mutations in TOP2B have a dominant negative effect on enzyme function, resulting in defective proliferation, survival of B-2 cells, causing a block in B cell development, and impair humoral function PMID:31409799

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

600 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4
VUS282
Likely Benign267
Benign11
Conflicting2
4
Pathogenic
282
VUS
267
Likely Benign
11
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
4
0
4
Likely Pathogenic
0
0
0
0
0
VUS
22
237
18
5
282
Likely Benign
1
3
149
114
267
Benign
0
0
10
1
11
Conflicting
—2
Total23240181120566

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

TOP2B · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Integrated Global Phosphoproteomic, Bioinformatic, and Machine Learning Analysis Reveals Regulatory Networks of TOP1, TOP2A, TOP2B, and C1orf35 in Hepatocellular Carcinoma (HCC).
Mestareehi A.·Oncol Res
2026
TOP2B modulates DNA supercoiling and chromatin contacts during transcriptional induction.
Terrón-Bautista J et al.·Sci Adv
2025Open Access
ATRX cooperates with TOP2B for replication fork stability and DNA damage response through G-quadruplex regulation.
Pang Y et al.·Nucleic Acids Res
2025Open Access
Infantile epileptic spasms syndrome as a new phenotype in TOP2B deficiency caused by a de novo variant: a case report and literature review.
Zhu GQ et al.·Front Pediatr
2025Open AccessReview
Top2b-Regulated Genes and Pathways Linked to Retinal Homeostasis and Degeneration.
Ibrahim MM et al.·Cells
2025Open Access
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients