Is CHRNB2 p.Cys470fs (c.1407_1410del) pathogenic?

CHRNB2 p.Cys470fs (c.14071410del) is classified Uncertain significance in CHRNB2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-03-26). Very rare (popmax 0.00267%, afr); Associated with familial sleep-related hypermotor epilepsy.

What condition is associated with CHRNB2 p.Cys470fs (c.1407_1410del)?

CHRNB2 p.Cys470fs (c.1407_1410del) is associated with familial sleep-related hypermotor epilepsy (ClinVar).

How common is CHRNB2 p.Cys470fs (c.1407_1410del) in the general population?

CHRNB2 p.Cys470fs (c.1407_1410del) is very rare (popmax 0.00267%, afr) (gnomAD).

How is Sleep-related hypermotor epilepsy inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

CHRNB2 p.Cys470fs

c.1407_1410del · rs796052332 · VCV205080

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

familial sleep-related hypermotor epilepsy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (6 of 6) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.1	GERP 2, phastCons 1
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,884 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000248% 4/1,614,024 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,442
East Asian	0.00223%	44,884
South Asian	0.0011%	91,086

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CHRNB2
Protein: p.Cys470fs
Coding: c.1407_1410del
MANE Select: NM_000748
dbSNP: rs796052332
Type: Deletion
Location: chr1:154575827 (GRCh38)
Gene constraint: LOEUF 1.116 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.16 · 15 PDB
Residue 470: an α-helix

Full CHRNB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

familial sleep-related hypermotor epilepsy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Sleep-related hypermotor epilepsy (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

CHRNB2 p.Cys470_Val471del Uncertain significance ★ same residue
CHRNB2 c.65-2del Uncertain significance ★★ same condition
CHRNB2 p.Cys245fs Uncertain significance ★★ same condition
CHRNB2 p.Glu371fs Uncertain significance ★★ same condition
CHRNB2 p.Val287_Pro289del Uncertain significance ★★ same condition
CHRNB2 p.Asn392fs Uncertain significance ★ same condition
CHRNB2 p.Asp217fs Uncertain significance ★ same condition
CHRNB2 p.Gln480del Uncertain significance ★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/chrnb2-p-cys470fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown