congenital myasthenic syndrome 2A

Summary

congenital myasthenic syndrome 2A (MONDO:0014581) is a disease caused by CHRNB1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: CHRNB1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 436

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital myasthenic syndrome 2A
Mondo ID	MONDO:0014581
OMIM	616313
DOID	DOID:0110681
UMLS	C4225374
MedGen	908185
GARD	0009895
Is cancer (heuristic)	no

Also known as: CMS IIa · CMS2A · congenital myasthenic syndrome type 2A · myasthenic syndrome, congenital, 2A, slow-channel · myasthenic syndrome, congenital, postsynaptic slow-channel · myasthenic syndrome, congenital, slow-channel · myasthenic syndrome, congenital, type IIa · SCCMS · slow channel congenital myasthenic syndrome

Data availability: 436 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › postsynaptic congenital myasthenic syndrome › congenital myasthenic syndrome 2A

Related subtypes (13): congenital myasthenic syndrome 10, congenital myasthenic syndrome 1A, congenital myasthenic syndrome 16, congenital myasthenic syndrome 8, congenital myasthenic syndrome 17, congenital myasthenic syndrome 2C, congenital myasthenic syndrome 3A, congenital myasthenic syndrome 3B, congenital myasthenic syndrome 3C, congenital myasthenic syndrome 9, congenital myasthenic syndrome 11, congenital myasthenic syndrome 19, congenital myasthenic syndrome 4

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

436 retrieved; paginated sample, class counts are floors:

224 uncertain significance, 138 likely benign, 31 conflicting classifications of pathogenicity, 12 pathogenic, 10 benign, 9 likely pathogenic, 8 benign/likely benign, 4 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1068934	NM_000747.3(CHRNB1):c.759dup (p.Ala254fs)	CHRNB1	Pathogenic	criteria provided, single submitter
1069201	NM_000747.3(CHRNB1):c.883del (p.Ala295fs)	CHRNB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1435639	NM_000747.3(CHRNB1):c.823G>T (p.Glu275Ter)	CHRNB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
18372	NM_000747.3(CHRNB1):c.865G>A (p.Val289Met)	CHRNB1	Pathogenic	criteria provided, multiple submitters, no conflicts
18373	NM_000747.3(CHRNB1):c.853C>A (p.Leu285Met)	CHRNB1	Pathogenic	criteria provided, single submitter
18374	NM_000747.3(CHRNB1):c.1347_1355del (p.Glu449_Glu451del)	CHRNB1	Pathogenic	criteria provided, single submitter
2023085	NM_000747.3(CHRNB1):c.1072_1073del (p.Leu358fs)	CHRNB1	Pathogenic	criteria provided, single submitter
2118016	NM_000747.3(CHRNB1):c.1102_1103del (p.Asp368fs)	CHRNB1	Pathogenic	criteria provided, single submitter
3703779	NM_000747.3(CHRNB1):c.270G>A (p.Trp90Ter)	CHRNB1	Pathogenic	criteria provided, single submitter
448999	NM_000747.3(CHRNB1):c.727C>T (p.Arg243Cys)	CHRNB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4702847	NM_000747.3(CHRNB1):c.863del (p.Thr288fs)	CHRNB1	Pathogenic	criteria provided, single submitter
504421	NM_000747.3(CHRNB1):c.1218-9_1218-7del	CHRNB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
584314	NC_000017.11:g.(?7454277)(7454540_?)del	CHRNB1	Pathogenic	criteria provided, single submitter
631787	NM_000747.3(CHRNB1):c.605dup (p.Ile203fs)	CHRNB1	Pathogenic	criteria provided, single submitter
651814	NC_000017.11:g.(?7454287)(7454530_?)del	CHRNB1	Pathogenic	criteria provided, single submitter
860460	NM_000747.3(CHRNB1):c.866T>C (p.Val289Ala)	CHRNB1	Pathogenic	criteria provided, single submitter
1349189	NM_000747.3(CHRNB1):c.854T>C (p.Leu285Pro)	CHRNB1	Likely pathogenic	criteria provided, single submitter
2144433	NM_000747.3(CHRNB1):c.611-1G>C	CHRNB1	Likely pathogenic	criteria provided, single submitter
2663945	NM_000747.3(CHRNB1):c.353+1del	CHRNB1	Likely pathogenic	criteria provided, single submitter
2701345	NM_000747.3(CHRNB1):c.757_820+135del	CHRNB1	Likely pathogenic	criteria provided, single submitter
3066140	NM_000747.3(CHRNB1):c.1071C>A (p.Tyr357Ter)	CHRNB1	Likely pathogenic	criteria provided, single submitter
3582827	NM_000747.3(CHRNB1):c.544C>T (p.Gln182Ter)	CHRNB1	Likely pathogenic	criteria provided, single submitter
3715131	NM_000747.3(CHRNB1):c.610+1G>A	CHRNB1	Likely pathogenic	criteria provided, single submitter
661296	NM_000747.3(CHRNB1):c.354-1G>A	CHRNB1	Likely pathogenic	criteria provided, single submitter
930319	NM_000747.3(CHRNB1):c.687_688insT (p.Gly230fs)	CHRNB1	Likely pathogenic	criteria provided, single submitter
1690747	NM_000747.3(CHRNB1):c.611-9C>G	CHRNB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
197164	NM_000747.3(CHRNB1):c.342G>A (p.Val114=)	CHRNB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1982120	NM_000747.3(CHRNB1):c.1005C>T (p.Arg335=)	CHRNB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2085396	NM_000747.3(CHRNB1):c.199-2A>C	CHRNB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
256775	NM_000747.3(CHRNB1):c.720C>T (p.Ile240=)	CHRNB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
CHRNB1	Definitive	Autosomal dominant	congenital myasthenic syndrome 2C	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CHRNB1	Orphanet:98913	Postsynaptic congenital myasthenic syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CHRNB1	HGNC:1961	ENSG00000170175	P11230	Acetylcholine receptor subunit beta	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CHRNB1	Acetylcholine receptor subunit beta	After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CHRNB1	Other/Unknown	no		Nicotinic_acetylcholine_rcpt, Neurotrans-gated_channel_TM, Neur_channel

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gastrocnemius	1
hindlimb stylopod muscle	1
muscle of leg	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CHRNB1	137	ubiquitous	marker	gastrocnemius, hindlimb stylopod muscle, muscle of leg

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CHRNB1	711

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CHRNB1	P11230	13

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
postsynaptic membrane organization	1	4213.0×	0.003	CHRNB1
behavioral response to nicotine	1	1872.4×	0.003	CHRNB1
nervous system process	1	1203.7×	0.003	CHRNB1
muscle cell development	1	936.2×	0.003	CHRNB1
synaptic transmission, cholinergic	1	802.5×	0.003	CHRNB1
monoatomic cation transport	1	766.0×	0.003	CHRNB1
acetylcholine receptor signaling pathway	1	624.1×	0.003	CHRNB1
neuromuscular synaptic transmission	1	601.9×	0.003	CHRNB1
skeletal muscle contraction	1	510.7×	0.003	CHRNB1
membrane depolarization	1	510.7×	0.003	CHRNB1
regulation of membrane potential	1	230.8×	0.005	CHRNB1
muscle contraction	1	208.1×	0.005	CHRNB1
monoatomic ion transmembrane transport	1	208.1×	0.005	CHRNB1
signal transduction	1	16.1×	0.062	CHRNB1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
CHRNB1	VARENICLINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CHRNB1	10	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VARENICLINE	4	CHRNB1
NICOTINE	4	CHRNB1
TROPISETRON	4	CHRNB1
BUPROPION	4	CHRNB1
MECAMYLAMINE	4	CHRNB1
DEXMECAMYLAMINE	3	CHRNB1
CYTISINICLINE	3	CHRNB1
RADAFAXINE	2	CHRNB1
GTS-21	2	CHRNB1
TC-2216	1	CHRNB1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
CHRNB1	87	Binding:51, Functional:36

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

10 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
VARENICLINE	4	CHRNB1
NICOTINE	4	CHRNB1
TROPISETRON	4	CHRNB1
BUPROPION	4	CHRNB1
MECAMYLAMINE	4	CHRNB1
DEXMECAMYLAMINE	3	CHRNB1
CYTISINICLINE	3	CHRNB1
RADAFAXINE	2	CHRNB1
GTS-21	2	CHRNB1
TC-2216	1	CHRNB1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CHRNB1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.