# NM_201590.3(CACNB2):c.15C>A (p.Arg5=)

https://sugi.bio/variant/cacnb2-p-arg5

## Summary

**CACNB2 p.Arg5= (c.15C>A)** is classified **Likely benign** in CACNB2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-14). Absent from gnomAD v4.1; Associated with Brugada syndrome 4.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs2132070434 · 2 submitters · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CACNB2 gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to Brugada syndrome 4.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Not applicable |
| Age of onset (of this condition) | Adult, Childhood |
| Prevalence | 1-5 / 10 000 (Europe) |

**Commonly reported features of Brugada syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Syncope — Frequent (79-30%)
- Cardiac arrest — Frequent (79-30%)
- Right bundle branch block — Frequent (79-30%)
- ST segment elevation — Frequent (79-30%)
- Tachycardia — Occasional (29-5%)
- Ventricular fibrillation — Occasional (29-5%)
- Paroxysmal ventricular tachycardia — Occasional (29-5%)
- Supraventricular tachycardia — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010362/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CACNB2](https://sugi.bio/atlas/gene/CACNB2/) |
| Protein change (HGVS p.) | p.Arg5= |
| Coding change (HGVS c.) | c.15C>A |
| MANE Select transcript | [NM_201596](https://www.ncbi.nlm.nih.gov/nuccore/NM_201596) (variant reported on NM_201590) |
| dbSNP | [rs2132070434](https://www.ncbi.nlm.nih.gov/snp/rs2132070434/) |
| Variant type | single nucleotide variant |
| Location | chr10:18340941-18340941 (GRCh38) |
| ClinVar | [VCV1094362](https://www.ncbi.nlm.nih.gov/clinvar/variation/1094362/) |

**All HGVS expressions:** `LRG_381:g.205265C>A`, `LRG_381t1:c.214-60983C>A`, `LRG_381t2:c.15C>A`, `NC_000010.10:g.18629870C>A`, `NC_000010.11:g.18340941C>A`, `NG_016195.1:g.205265C>A`, `NM_000724.4:c.49-60983C>A`, `NM_001167945.2:c.130-60983C>A`, `NM_001330060.2:c.49-60983C>A`, `NM_201571.4:c.130-60983C>A`, `NM_201572.4:c.130-60983C>A`, `NM_201590.3:c.15C>A`, `NM_201593.3:c.214-60983C>A`, `NM_201596.3:c.214-60983C>A`, `NM_201597.3:c.214-60983C>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 (below), not from a missing predictor score.
- Conservation: phyloP 3.037, GERP -1.38, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 15.99**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**CACNB2** population constraint: LOEUF 0.77, pLI 9.0033e-06, missense-Z -0.71303. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **cardiogenetic disease** — Disputed (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 65.78, 38% of residues very-high.

**3 experimental structure(s)** (PDB): [8HLP](https://www.rcsb.org/structure/8HLP), [8HMA](https://www.rcsb.org/structure/8HMA), [8HMB](https://www.rcsb.org/structure/8HMB).

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

*Describes the biological roles of CACNB2 (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:** CACNB2's established molecular role includes voltage-gated calcium channel activity.


### Pathways affected {#pathways}

CACNB2 participates in **8 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Phase 0 - rapid depolarisation](https://reactome.org/content/detail/R-HSA-5576892) | curated |
| [Phase 2 - plateau phase](https://reactome.org/content/detail/R-HSA-5576893) | curated |
| [Presynaptic depolarization and calcium channel opening](https://reactome.org/content/detail/R-HSA-112308) | curated |
| [Adrenaline,noradrenaline inhibits insulin secretion](https://reactome.org/content/detail/R-HSA-400042) | electronic |
| [Mechanical load activates signaling by PIEZO1 and integrins in osteocytes](https://reactome.org/content/detail/R-HSA-9856532) | electronic |
| [NCAM1 interactions](https://reactome.org/content/detail/R-HSA-419037) | electronic |
| [Regulation of insulin secretion](https://reactome.org/content/detail/R-HSA-422356) | electronic |
| [Sensory processing of sound by inner hair cells of the cochlea](https://reactome.org/content/detail/R-HSA-9662360) | electronic |

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

**Molecular function:** voltage-gated calcium channel activity.

**Biological process:** positive regulation of calcium ion transport, calcium ion import, membrane depolarization during AV node cell action potential, regulation of heart rate by cardiac conduction, membrane depolarization during atrial cardiac muscle cell action potential.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-05-14.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2021–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2021-05-06 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-05-14 |

## Associated conditions {#conditions}

[Brugada syndrome 4](https://sugi.bio/atlas/disease/brugada-syndrome-4/).

**Reported phenotype names (ClinVar):** Brugada syndrome 4, Cardiovascular phenotype.

## Similar variants {#similar}

Related CACNB2 variant pages (same residue, condition, or type): [CACNB2 p.Arg5Cys](/variant/cacnb2-p-arg5cys), [CACNB2 p.Arg5Gly](/variant/cacnb2-p-arg5gly), [CACNB2 c.1206+5G>A](/variant/cacnb2-c-1206-plus-5g-a), [CACNB2 c.1303-3C>T](/variant/cacnb2-c-1303-minus-3c-t), [CACNB2 c.1488+6G>A](/variant/cacnb2-c-1488-plus-6g-a), [CACNB2 p.Ala105Thr](/variant/cacnb2-p-ala105thr), [CACNB2 p.Ala118Val](/variant/cacnb2-p-ala118val), [CACNB2 p.Ala128Val](/variant/cacnb2-p-ala128val).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 2026-07-14); 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 1094362). 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.*