# NM_000742.4(CHRNA2):c.246C>T (p.Asp82=)

https://sugi.bio/variant/chrna2-p-asp82

## Summary

**CHRNA2 p.Asp82= (c.246C>T)** is classified **Likely benign** in CHRNA2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-08). Ultra-rare (popmax 0.0333%, amr); Associated with familial sleep-related hypermotor epilepsy.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs201244136 · 3 submitters · 1 linked condition · ultra-rare (popmax 0.0333%, amr)

## For patients & families {#patients}

This is a change in the CHRNA2 gene that is classified as likely benign — not considered disease-causing, submitted by 3 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 | CHRNA2 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 | [CHRNA2](https://sugi.bio/atlas/gene/CHRNA2/) |
| Protein change (HGVS p.) | p.Asp82= |
| Coding change (HGVS c.) | c.246C>T |
| MANE Select transcript | [NM_000742](https://www.ncbi.nlm.nih.gov/nuccore/NM_000742) |
| dbSNP | [rs201244136](https://www.ncbi.nlm.nih.gov/snp/rs201244136/) |
| Variant type | single nucleotide variant |
| Location | chr8:27469809-27469809 (GRCh38) |
| ClinVar | [VCV388375](https://www.ncbi.nlm.nih.gov/clinvar/variation/388375/) |

**All HGVS expressions:** `NC_000008.10:g.27327326G>A`, `NC_000008.11:g.27469809G>A`, `NG_015827.1:g.14488C>T`, `NM_000742.4:c.246C>T`, `NM_001282455.2:c.246C>T`, `NM_001347705.2:c.-182C>T`, `NM_001347706.2:c.-227C>T`, `NM_001347707.2:c.-168C>T`, `NM_001347708.2:c.-216C>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 (below), not from a missing predictor score.
- Conservation: phyloP -6.39, GERP -4.17 — fast-evolving / accelerated position
- CADD: **PHRED 2.011**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.21 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0333%** (amr) · FAF95 0.0221% · FAF99 0.0184% · 20/60,026 in the highest group · 114/1,614,190 alleles overall — ultra-rare (popmax 0.0333%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0878% | 1,139 |
| Admixed American (grpmax) | 0.0333% | 3,001 |
| Remaining individuals (not grpmax-eligible) | 0.0224% | 4,465 |
| African / African-American | 0.00799% | 12,509 |
| European (non-Finnish) | 0.00373% | 26,819 |
| South Asian | 0.00329% | 30,363 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,012 |

Ashkenazi Jewish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**CHRNA2** population constraint: LOEUF 1.195, pLI 1.7932e-12, missense-Z 0.89981. *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** — Limited (AD)
- **benign familial infantile epilepsy** — Disputed (AD)

## Protein context {#protein}

Residue **82** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 77.88, 50% of residues very-high.

**1 experimental structure(s)** (PDB): [5FJV](https://www.rcsb.org/structure/5FJV).

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

*Describes the biological roles of CHRNA2 (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:** CHRNA2's established molecular role includes acetylcholine receptor activity.


### Pathways affected {#pathways}

CHRNA2 participates in **2 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 |

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

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

**Biological process:** signal transduction, acetylcholine receptor signaling pathway.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-08.

**Submitter consensus:** unanimous (3/3 Likely benign).

**Submission history:** 3 submissions (2018–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2021-06-21 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2018-07-26 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-08 |

## 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, Inborn genetic diseases, Autosomal Dominant Sleep-Related Hypermotor (Hyperkinetic) Epilepsy, none provided.

## Similar variants {#similar}

Related CHRNA2 variant pages (same residue, condition, or type): [CHRNA2 p.Asp82Gly](/variant/chrna2-p-asp82gly), [CHRNA2 c.1464+4C>T](/variant/chrna2-c-1464-plus-4c-t), [CHRNA2 c.1464+5G>A](/variant/chrna2-c-1464-plus-5g-a), [CHRNA2 c.294+1G>A](/variant/chrna2-c-294-plus-1g-a), [CHRNA2 c.294+5G>A](/variant/chrna2-c-294-plus-5g-a), [CHRNA2 c.449+3A>T](/variant/chrna2-c-449-plus-3a-t), [CHRNA2 c.73+4A>C](/variant/chrna2-c-73-plus-4a-c), [CHRNA2 p.Ala177Pro](/variant/chrna2-p-ala177pro).

### 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 388375). 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.*