# NM_000748.3(CHRNB2):c.811_812del (p.Val272fs)

https://sugi.bio/variant/chrnb2-p-val272fs

## Summary

**CHRNB2 p.Val272fs (c.811_812del)** is classified **Uncertain significance** in CHRNB2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-03-07). Very rare (popmax 0.00167%, amr); Associated with familial sleep-related hypermotor epilepsy.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs2526370163 · 2 submitters · 1 linked condition · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the CHRNB2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to familial sleep-related hypermotor epilepsy.

*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 |
| Age of onset (of this condition) | Adolescent, Adult, Childhood |
| Diagnostic panels | CHRNB2 is a diagnostic-grade gene on 4 Genomics England panels |

**Commonly reported features of Sleep-related hypermotor epilepsy** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Nocturnal seizures — Very frequent (99-80%)
- Abnormal repetitive mannerisms — Frequent (79-30%)
- Paroxysmal dystonia — Frequent (79-30%)
- Involuntary movements — Frequent (79-30%)
- Urinary incontinence — Occasional (29-5%)
- Depression — Occasional (29-5%)
- Anxiety — Occasional (29-5%)
- Hyperventilation — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0022703/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CHRNB2](https://sugi.bio/atlas/gene/CHRNB2/) |
| Protein change (HGVS p.) | p.Val272fs |
| Coding change (HGVS c.) | c.811_812del |
| MANE Select transcript | [NM_000748](https://www.ncbi.nlm.nih.gov/nuccore/NM_000748) |
| dbSNP | [rs2526370163](https://www.ncbi.nlm.nih.gov/snp/rs2526370163/) |
| Variant type | Microsatellite |
| Location | chr1:154571632-154571633 (GRCh38) |
| ClinVar | [VCV2172430](https://www.ncbi.nlm.nih.gov/clinvar/variation/2172430/) |

**All HGVS expressions:** `NC_000001.10:g.154544108TC[1]`, `NC_000001.11:g.154571632TC[1]`, `NG_008027.1:g.8852TC[1]`, `NM_000748.2:c.811_812del`, `NM_000748.3:c.811_812del`

## 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 11.219, GERP 1.99, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.116, pLI 1.6832e-09. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 5 of 6**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00167%** (amr) · 1/60,030 in the highest group · 1/1,461,890 alleles overall — very rare (popmax 0.00167%, amr).

*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}

**CHRNB2** population constraint: LOEUF 1.116, pLI 1.6832e-09, missense-Z 1.0117. *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):

- **familial sleep-related hypermotor epilepsy** — Definitive (AD)

## Protein context {#protein}

Residue **272** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 81.16, 51% of residues very-high.

**15 experimental structure(s)** (PDB): [2K58](https://www.rcsb.org/structure/2K58), [2K59](https://www.rcsb.org/structure/2K59), [2KSR](https://www.rcsb.org/structure/2KSR), [2LM2](https://www.rcsb.org/structure/2LM2), [5KXI](https://www.rcsb.org/structure/5KXI), [6CNJ](https://www.rcsb.org/structure/6CNJ).

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

*Describes the biological roles of CHRNB2 (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:** CHRNB2's established molecular role includes acetylcholine receptor activity.


### Pathways affected {#pathways}

CHRNB2 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Highly calcium permeable nicotinic acetylcholine receptors](https://reactome.org/content/detail/R-HSA-629597) | curated |
| [Highly calcium permeable postsynaptic nicotinic acetylcholine receptors](https://reactome.org/content/detail/R-HSA-629594) | curated |
| [Highly sodium permeable postsynaptic acetylcholine nicotinic receptors](https://reactome.org/content/detail/R-HSA-629587) | curated |

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

**Molecular function:** acetylcholine receptor activity, acetylcholine-gated monoatomic cation-selective channel activity, acetylcholine binding.

**Biological process:** response to hypoxia, signal transduction, synaptic transmission, cholinergic, learning, memory, visual learning.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-03-07.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2022–2023); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-03-07 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-08-09 |

## Associated conditions {#conditions}

[familial sleep-related hypermotor epilepsy](https://sugi.bio/atlas/disease/familial-sleep-related-hypermotor-epilepsy/).

**Reported phenotype names (ClinVar):** Familial sleep-related hypermotor epilepsy, not provided, Autosomal Dominant Sleep-Related Hypermotor (Hyperkinetic) Epilepsy, none provided.

## Similar variants {#similar}

Related CHRNB2 variant pages (same residue, condition, or type): [CHRNB2 p.Lys265del](/variant/chrnb2-p-lys265del), [CHRNB2 p.Asn122del](/variant/chrnb2-p-asn122del), [CHRNB2 p.Ser448fs](/variant/chrnb2-p-ser448fs), [CHRNB2 p.Val287Leu](/variant/chrnb2-p-val287leu), [CHRNB2 p.Val287Met](/variant/chrnb2-p-val287met), [CHRNB2 p.Val308Ala](/variant/chrnb2-p-val308ala), [CHRNB2 c.1338+3G>T](/variant/chrnb2-c-1338-plus-3g-t), [CHRNB2 c.366-3C>T](/variant/chrnb2-c-366-minus-3c-t).

### 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 2172430). 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.*