CHRNA4

protein-coding

cholinergic receptor nicotinic alpha 4 subunit, the group of Cholinergic receptors nicotinic subunits

Gene summary

This gene encodes a nicotinic acetylcholine receptor, which belongs to a superfamily of ligand-gated ion channels that play a role in fast signal transmission at synapses. These pentameric receptors can bind acetylcholine, which causes an extensive change in conformation that leads to the opening of an ion-conducting channel across the plasma membrane. This protein is an integral membrane receptor subunit that can interact with either nAChR beta-2 or nAChR beta-4 to form a functional receptor. Mutations in this gene cause nocturnal frontal lobe epilepsy type 1. Polymorphisms in this gene that provide protection against nicotine addiction have been described. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2012]

Previous symbols:

EBN
EBN1

MANE transcript

NM_000744.7

Inheritance

ClinVar variants

P:8U:459B:477

Top phenotype

Epilepsy, nocturnal frontal lobe, type 1

gnomAD constraint

pLI —, LoF o/e 0.48

Max pathogenic AF

—

Genomic locus

chr20:63,343,223-63,378,401

External References & Databases

Ensembl (ENSG00000101204)

Transcript & Mutation Effects

hg38 • Region Span ~35.2 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

familial sleep-related hypermotor epilepsyDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000030

Submitter: ClinGen

CHRNA4 was reported in relation to autosomal dominant nocturnal frontal lobe epilepsy in 1995 (PMID: 7550350). At least 7 unique variants (missense, small insertion) have been reported in humans. "So far, nearly all of the AD nocturnal frontal lobe epilepsy mutations identified within CHRNA4 are missense mutations that cause amino acid exchanges within the second, less often the first, transmembrane domain" (PMID: 25194481). This gene-disease relationship is supported by case-level data and experimental data including functional alteration studies and a mouse model. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. In summary, CHRNA4 is definitively associated with autosomal dominant nocturnal frontal lobe epilepsy.

autosomal dominant nocturnal frontal lobe epilepsySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0020300

Submitter: Orphanet

autosomal dominant nocturnal frontal lobe epilepsy 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0010899

Submitter: G2P

autosomal dominant nocturnal frontal lobe epilepsy 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0010899

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Epilepsy, nocturnal frontal lobe, type 1AD

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: Mildly affected individuals have been described as frequently undiagnosed/misdiagnosed as nightmares/other sleep disorders, and thus genetic diagnosis may be helpful

Refs: 7647781; 7550350; 10563623; 14623738; 20301348; 21753767

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CHRNA4 variants in ClinVar

13 Conditions Cataloged

Familial sleep-related hypermotor epilepsyTotal: 894

not providedTotal: 372

Inborn genetic diseasesTotal: 204

not specifiedTotal: 153

Autosomal dominant nocturnal frontal lobe epilepsy 1Total: 73

Tobacco use disorderTotal: 43

CHRNA4-related disorderTotal: 39

Tobacco addiction, susceptibility toTotal: 22

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000744.7. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			11 clinvar	293 clinvar	6 clinvar	310
missense	2 clinvar	5 clinvar	412 clinvar	173 clinvar	1 clinvar	593
nonsense			12 clinvar	1 clinvar		13
start loss			2 clinvar			2
frameshift		1 clinvar	17 clinvar	3 clinvar		21
splice donor/acceptor (+/-2bp)			5 clinvar			5
Total	2	6	459	470	7	944

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 7 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000744.7	RefSeq	NP_000735.1	6	MANE Select
ENST00000370263.9	Ensembl	ENSP00000359285.4	6	MANE Select
NM_001256573.2	RefSeq	NP_001243502.1	2	Standard
ENST00000498043.6	Ensembl	ENSP00000429513.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Nicotine addiction - Homo sapiens (human)
Neuroactive ligand-receptor interaction - Homo sapiens (human)
Cholinergic synapse - Homo sapiens (human)
Nicotine Pathway (Dopaminergic Neuron), Pharmacodynamics
Levomethadyl Acetate Action Action Pathway

Biological Process

action potential
response to hypoxia
DNA repair
ion transport
calcium ion transport

Molecular Function

extracellular ligand-gated ion channel activity
protein binding
ligand-gated ion channel activity
acetylcholine receptor activity
acetylcholine-gated cation-selective channel activity

Cellular Component

plasma membrane
integral component of plasma membrane
acetylcholine-gated channel complex
external side of plasma membrane
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000370263
Coding exons: 6
Length: 34334
Individuals with no LoFs: 125656
Homozygous LoFs: 0
Heterozygous LoFs: 30
Defined: 125686
p: 0.000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.342	377	396	0.952	0.0000302	4017
Missense (PolyPhen)		153	184.52	0.8292		1846
Synonymous	-2.33	225	185	1.22	0.0000157	1336
Loss of Function	2.17	10	20.6	0.485	9.85e-7	227

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00020	0.00018	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00011	0.00011	rare
Finnish	0.00028	0.00028	rare
European (Non-Finnish)	0.00015	0.00015	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: 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 permeable to sodium ions. {ECO:0000269|PubMed:22361591}.;
Disease: DISEASE: Epilepsy, nocturnal frontal lobe, 1 (ENFL1) [MIM:600513]: An autosomal dominant focal epilepsy characterized by nocturnal seizures with hyperkinetic automatisms and poorly organized stereotyped movements. {ECO:0000269|PubMed:10563623, ECO:0000269|PubMed:14623738, ECO:0000269|PubMed:7550350}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.109

Intolerance Scores

LoFtool: 0.0988
RVIS EVS: -1.97
RVIS percentile EVS: 1.79

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.682

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium