CHRNA4

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

Basic information

Region (hg38): 20:63343223-63378401

Previous symbols: [ "EBN", "EBN1" ]

Links

ENSG00000101204 ∙ NCBI:1137 ∙ OMIM:118504 ∙ HGNC:1958 ∙ Uniprot:P43681 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• autosomal dominant nocturnal frontal lobe epilepsy 1 (Definitive), mode of inheritance: AD
• autosomal dominant nocturnal frontal lobe epilepsy 1 (Strong), mode of inheritance: AD
• autosomal dominant nocturnal frontal lobe epilepsy (Supportive), mode of inheritance: AD
• sleep-related hypermotor epilepsy (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Epilepsy, nocturnal frontal lobe, type 1	AD	General	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	Neurologic	7647781; 7550350; 10563623; 14623738; 20301348; 21753767
Mildly affected individuals have been described as frequently undiagnosed/misdiagnosed as nightmares/other sleep disorders, and thus genetic diagnosis may be helpful

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the CHRNA4 gene.

• Autosomal dominant nocturnal frontal lobe epilepsy (2 variants)
• Autosomal dominant nocturnal frontal lobe epilepsy 1 (2 variants)
• not provided (2 variants)
• Inborn genetic diseases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CHRNA4 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			7	251	14	272
missense	2	2	326	75	1	406
nonsense			9			9
start loss			2			2
frameshift		1	15	2		18
inframe indel			11			11
splice donor/acceptor (+/-2bp)			4			4
splice region			5	12	2	19
non coding			5	76	82	163
Total	2	3	379	404	97

Variants in CHRNA4

This is a list of pathogenic ClinVar variants found in the CHRNA4 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
20-63346204-G-A		Autosomal dominant nocturnal frontal lobe epilepsy • Tobacco addiction, susceptibility to;Autosomal dominant nocturnal frontal lobe epilepsy 1	Benign (Jan 29, 2024)
20-63346437-G-A			Benign (Feb 14, 2021)
20-63346482-C-T			Likely benign (Jun 14, 2018)
20-63346483-G-A			Benign (May 30, 2020)
20-63346486-G-A			Benign (Mar 28, 2020)
20-63346520-A-C			Benign (Jun 23, 2021)
20-63346521-G-C			Benign (Feb 06, 2021)
20-63346594-C-G			Benign (Mar 19, 2020)
20-63346624-G-A			Benign (Apr 29, 2020)
20-63346719-G-A			Likely benign (Feb 01, 2017)
20-63346733-C-G			Likely benign (Aug 14, 2018)
20-63346755-G-A		Autosomal dominant nocturnal frontal lobe epilepsy	Likely benign (Mar 10, 2016)
20-63346758-A-G		Autosomal dominant nocturnal frontal lobe epilepsy	Uncertain significance (Dec 18, 2022)
20-63346761-G-A		Inborn genetic diseases	Uncertain significance (Mar 28, 2024)
20-63346761-G-T		Autosomal dominant nocturnal frontal lobe epilepsy • Autosomal dominant nocturnal frontal lobe epilepsy 1	Conflicting classifications of pathogenicity (Jan 06, 2024)
20-63346762-C-T		Autosomal dominant nocturnal frontal lobe epilepsy	Likely benign (Aug 21, 2022)
20-63346763-G-A		Autosomal dominant nocturnal frontal lobe epilepsy	Uncertain significance (Nov 27, 2023)
20-63346763-G-C		Autosomal dominant nocturnal frontal lobe epilepsy	Uncertain significance (Jan 14, 2022)
20-63346764-G-A		Autosomal dominant nocturnal frontal lobe epilepsy	Uncertain significance (Jul 12, 2022)
20-63346767-G-A		Autosomal dominant nocturnal frontal lobe epilepsy	Likely benign (Oct 23, 2023)
20-63346768-G-C		Autosomal dominant nocturnal frontal lobe epilepsy • Inborn genetic diseases	Uncertain significance (Feb 08, 2024)
20-63346774-G-C		Autosomal dominant nocturnal frontal lobe epilepsy	Likely benign (Sep 23, 2022)
20-63346775-C-A		Autosomal dominant nocturnal frontal lobe epilepsy	Uncertain significance (May 02, 2023)
20-63346780-C-T		Autosomal dominant nocturnal frontal lobe epilepsy	Conflicting classifications of pathogenicity (Dec 10, 2022)
20-63346781-G-A		Autosomal dominant nocturnal frontal lobe epilepsy	Uncertain significance (Mar 11, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CHRNA4	protein_coding	protein_coding	ENST00000370263	6	34334

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0000855	0.985	125656	0	30	125686	0.000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.342	377	396	0.952	0.0000302	4017
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000197	0.000185
Ashkenazi Jewish	0.000200	0.000198
East Asian	0.000109	0.000109
Finnish	0.000277	0.000277
European (Non-Finnish)	0.000153	0.000150
Middle Eastern	0.000109	0.000109
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

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.
• Pathway: 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;Fluoxetine Action Pathway;Citalopram Action Pathway;Escitalopram Action Pathway;Imipramine Action Pathway;Desipramine Action Pathway;Levallorphan Action Pathway;Dimethylthiambutene Action Pathway;Ethylmorphine Action Pathway;Pentazocine Action Pathway;Naltrexone Action Pathway;Buprenorphine Action Pathway;Alvimopan Action Pathway;Naloxone Action Pathway;Dihydromorphine Action Pathway;Nicotine Metabolism Pathway;Nicotine Action Pathway;Nalbuphine Action Pathway;Ketobemidone Action Pathway;Lidocaine (Local Anaesthetic) Action Pathway;Mepivacaine Action Pathway;Chloroprocaine Action Pathway;Cocaine Action Pathway;Dibucaine Action Pathway;Levobupivacaine Action Pathway;Benzocaine Action Pathway;Bupivacaine Action Pathway;Levorphanol Action Pathway;Propoxyphene Action Pathway;Tramadol Action Action Pathway;Diphenoxylate Action Pathway;Anileridine Action Pathway;Methadone Action Pathway;Oxycodone Action Pathway;Oxybuprocaine Action Pathway;Prilocaine Action Pathway;Procaine Action Pathway;Proparacaine Action Pathway;Ropivacaine Action Pathway;Codeine Action Pathway;Morphine Action Pathway;Heroin Action Pathway;Alfentanil Action Pathway;Oxymorphone Action Pathway;Hydrocodone Action Pathway;Hydromorphone Action Pathway;Sufentanil Action Pathway;Remifentanil Action Pathway;Fentanyl Action Pathway;Carfentanil Action Pathway;3-Methylthiofentanyl Action Pathway;Methadyl Acetate Action Pathway;Dezocine Action Pathway;Nicotine Activity on Dopaminergic Neurons;Sudden Infant Death Syndrome (SIDS) Susceptibility Pathways;Highly sodium permeable acetylcholine nicotinic receptors;Neuronal System;Neurotransmitter receptors and postsynaptic signal transmission;Transmission across Chemical Synapses;Highly calcium permeable nicotinic acetylcholine receptors;Presynaptic nicotinic acetylcholine receptors;Highly calcium permeable postsynaptic nicotinic acetylcholine receptors;Postsynaptic nicotinic acetylcholine receptors;Activation of Nicotinic Acetylcholine Receptors;Acetylcholine binding and downstream events (Consensus)

Recessive Scores

• pRec: 0.109

Intolerance Scores

• loftool: 0.0988
• rvis_EVS: -1.97
• rvis_percentile_EVS: 1.79

Haploinsufficiency Scores

• pHI: 0.126
• hipred: Y
• hipred_score: 0.538
• ghis: 0.633

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.682

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Chrna4
• Phenotype: nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); immune system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); hematopoietic system phenotype; homeostasis/metabolism phenotype

Gene ontology

• Biological process: action potential;response to hypoxia;DNA repair;ion transport;calcium ion transport;response to oxidative stress;signal transduction;chemical synaptic transmission;synaptic transmission, cholinergic;neuromuscular synaptic transmission;respiratory gaseous exchange;locomotory behavior;regulation of dopamine secretion;sensory perception of pain;ion transmembrane transport;response to nicotine;behavioral response to nicotine;exploration behavior;B cell activation;regulation of membrane potential;nervous system process;cognition;membrane depolarization;excitatory postsynaptic potential;inhibitory postsynaptic potential;acetylcholine receptor signaling pathway;regulation of synaptic vesicle exocytosis
• Cellular component: plasma membrane;integral component of plasma membrane;acetylcholine-gated channel complex;external side of plasma membrane;membrane;integral component of membrane;cell junction;dendrite;neuron projection;neuronal cell body;synapse;postsynaptic membrane;dopaminergic synapse;integral component of presynaptic membrane
• Molecular function: extracellular ligand-gated ion channel activity;protein binding;ligand-gated ion channel activity;acetylcholine receptor activity;acetylcholine-gated cation-selective channel activity;acetylcholine binding