# NM_004701.4(CCNB2):c.267G>A (p.Lys89=)

https://sugi.bio/variant/ccnb2-p-lys89

## Summary

**CCNB2 p.Lys89= (c.267G>A)** is classified **Benign** in CCNB2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2018-06-26). Low-frequency (popmax 1.15%, nfe).

**At a glance:** Benign · review: Multiple submitters · rsID rs35033821 · 3 submitters · low-frequency (popmax 1.15%, nfe)

## For patients & families {#patients}

This is a change in the CCNB2 gene that is classified as benign — not considered disease-causing, submitted by 3 submitters.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CCNB2](https://sugi.bio/atlas/gene/CCNB2/) |
| Protein change (HGVS p.) | p.Lys89= |
| Coding change (HGVS c.) | c.267G>A |
| MANE Select transcript | [NM_004701](https://www.ncbi.nlm.nih.gov/nuccore/NM_004701) |
| dbSNP | [rs35033821](https://www.ncbi.nlm.nih.gov/snp/rs35033821/) |
| Variant type | single nucleotide variant |
| Location | chr15:59107670-59107670 (GRCh38) |
| ClinVar | [VCV777248](https://www.ncbi.nlm.nih.gov/clinvar/variation/777248/) |

**All HGVS expressions:** `NC_000015.10:g.59107670G>A`, `NC_000015.9:g.59399869G>A`, `NM_004701.4:c.267G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.24) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 9.863, GERP 3.5, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 22.1**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.21**, acceptor gain **0.00**, donor gain **0.24**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.21**, acceptor gain **0.00**, donor gain **0.24**.
- Pangolin: Δ**0.68** (loss), gain 0.26 / loss 0.68. SpliceAI calls gain. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **1.15%** (nfe) · FAF95 1.13% · FAF99 1.12% · 13,528/1,178,562 in the highest group · 14,554/1,611,998 alleles overall — low-frequency (popmax 1.15%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 1.15% | 87 |
| Remaining individuals (not grpmax-eligible) | 0.713% | 140 |
| Finnish (not grpmax-eligible) | 0.343% | 292 |
| Admixed American | 0.276% | 362 |
| African / African-American | 0.171% | 586 |
| Middle Eastern | 0.0826% | 1,211 |
| South Asian | 0.0561% | 1,783 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.044% | 2,275 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**CCNB2** population constraint: LOEUF 1.013, pLI 8.9144e-10, missense-Z 0.19093. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 80.14, 69% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of CCNB2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** CCNB2's established molecular role includes cadherin binding.


### Pathways affected {#pathways}

CCNB2 participates in **11 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Activation of NIMA Kinases NEK9, NEK6, NEK7](https://reactome.org/content/detail/R-HSA-2980767) | curated |
| [Cyclin A/B1/B2 associated events during G2/M transition](https://reactome.org/content/detail/R-HSA-69273) | curated |
| [G2/M DNA replication checkpoint](https://reactome.org/content/detail/R-HSA-69478) | curated |
| [Initiation of Nuclear Envelope (NE) Reformation](https://reactome.org/content/detail/R-HSA-2995383) | curated |
| [Nuclear Pore Complex (NPC) Disassembly](https://reactome.org/content/detail/R-HSA-3301854) | curated |
| [Polo-like kinase mediated events](https://reactome.org/content/detail/R-HSA-156711) | curated |
| [Regulation of PLK1 Activity at G2/M Transition](https://reactome.org/content/detail/R-HSA-2565942) | curated |
| [Resolution of Sister Chromatid Cohesion](https://reactome.org/content/detail/R-HSA-2500257) | curated |
| [The role of GTSE1 in G2/M progression after G2 checkpoint](https://reactome.org/content/detail/R-HSA-8852276) | curated |
| [Condensation of Prometaphase Chromosomes](https://reactome.org/content/detail/R-HSA-2514853) | electronic |
| [Golgi Cisternae Pericentriolar Stack Reorganization](https://reactome.org/content/detail/R-HSA-162658) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** cadherin binding.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2018-06-26.

**Submitter consensus:** unanimous (2/2 Benign).

**Submission history:** 49 submissions (2018); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2018-06-26 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |

**Reported phenotype names (ClinVar):** not provided, Uterine corpus endometrial carcinoma, Clear cell carcinoma of kidney, Uveal melanoma, Lung cancer, Cervical cancer, Uterine carcinosarcoma, Thymoma, Thyroid cancer, nonmedullary, 1, Melanoma.

## Similar variants {#similar}

Related CCNB2 variant pages (same residue, condition, or type): [CCNB2 p.Ile395Thr](/variant/ccnb2-p-ile395thr), [CCNB2 p.Met100Thr](/variant/ccnb2-p-met100thr), [CCNB2 p.Ala112Gly](/variant/ccnb2-p-ala112gly), [CCNB2 p.Ala167Thr](/variant/ccnb2-p-ala167thr), [CCNB2 p.Ala46Thr](/variant/ccnb2-p-ala46thr), [CCNB2 p.Arg164Cys](/variant/ccnb2-p-arg164cys), [CCNB2 p.Arg164His](/variant/ccnb2-p-arg164his), [CCNB2 p.Arg196Gln](/variant/ccnb2-p-arg196gln).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 777248). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*