# NM_000748.3(CHRNB2):c.1338C>T (p.Ser446=)

https://sugi.bio/variant/chrnb2-p-ser446

## Summary

**CHRNB2 p.Ser446= (c.1338C>T)** is classified **Uncertain significance** in CHRNB2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-16). Very rare (popmax 0.00196%, amr); Associated with familial sleep-related hypermotor epilepsy.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs201462348 · 2 submitters · 1 linked condition · very rare (popmax 0.00196%, 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.Ser446= |
| Coding change (HGVS c.) | c.1338C>T |
| MANE Select transcript | [NM_000748](https://www.ncbi.nlm.nih.gov/nuccore/NM_000748) |
| dbSNP | [rs201462348](https://www.ncbi.nlm.nih.gov/snp/rs201462348/) |
| Variant type | single nucleotide variant |
| Location | chr1:154572161-154572161 (GRCh38) |
| ClinVar | [VCV1511375](https://www.ncbi.nlm.nih.gov/clinvar/variation/1511375/) |

**All HGVS expressions:** `NC_000001.10:g.154544637C>T`, `NC_000001.11:g.154572161C>T`, `NG_008027.1:g.9381C>T`, `NM_000748.3:c.1338C>T`

## 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 0.22) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP -1.954, GERP -3.61 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 12.09**. 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 **0.00**, acceptor gain **0.00**, donor gain **0.22**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.22**.
- Population frequency (gnomAD v4.1): grpmax **0.00196%** (amr) · FAF95 2.9e-05% · FAF99 1.1e-05% · 1/50,946 in the highest group · 5/1,536,956 alleles overall — very rare (popmax 0.00196%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00196% | 50,946 |
| African / African-American | 0.00137% | 73,054 |
| South Asian | 0.00119% | 83,976 |
| European (non-Finnish) | 0.000174% | 573,250 |

*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}


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 2025-07-16.

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

**Submission history:** 2 submissions (2023–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-07-16 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-12-11 |

## 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.Ser446Gly](/variant/chrnb2-p-ser446gly), [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), [CHRNB2 p.Ala135Val](/variant/chrnb2-p-ala135val), [CHRNB2 p.Ala154Thr](/variant/chrnb2-p-ala154thr).

### 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 1511375). 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.*