CHRNA1

cholinergic receptor nicotinic alpha 1 subunit, the group of Cholinergic receptors nicotinic subunits

Basic information

Region (hg38): 2:174747591-174787935

Previous symbols: [ "CHRNA" ]

Links

ENSG00000138435 ∙ NCBI:1134 ∙ OMIM:100690 ∙ HGNC:1955 ∙ Uniprot:P02708 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• lethal multiple pterygium syndrome (Strong), mode of inheritance: AR
• congenital myasthenic syndrome 1A (Strong), mode of inheritance: AD
• myasthenic syndrome, congenital, 1B, fast-channel (Strong), mode of inheritance: AD
• myasthenic syndrome, congenital, 1B, fast-channel (Strong), mode of inheritance: AR
• congenital myasthenic syndrome 1A (Strong), mode of inheritance: AD
• myasthenic syndrome, congenital, 1B, fast-channel (Strong), mode of inheritance: AR
• lethal multiple pterygium syndrome (Supportive), mode of inheritance: AR
• postsynaptic congenital myasthenic syndrome (Supportive), mode of inheritance: AR
• myasthenic syndrome, congenital, 1B, fast-channel (Strong), mode of inheritance: AR
• congenital myasthenic syndrome 1A (Strong), mode of inheritance: AD
• lethal multiple pterygium syndrome (Limited), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Myasthenic syndrome, congenital, 1A, slow-channel; Myasthenic syndrome, congenital, 1B, fast-channel	AD/AR	Musculoskeletal; Neurologic; Pharmacogenomic	Most individuals with CMS benefit from AChE inhibitors and/or potassium channel blocker 3,4-diaminopyridine (3,4-DAP), though caution must be used in giving 3,4-DAP to young children and individuals with fast-channel syndromes; For Slow-channel congenital myasthenic syndrome, effective treatment has been reported with therapies such as quinidine, fluoxetine, and ephedrine, while cholinesterase inhibitors and amifampridine should be avoided; Additional neurologic monitoring in pregnancy may be beneficial	Musculoskeletal; Neurologic	7254233; 3651795; 7863154; 7619526; 8872460; 9158151; 9221765; 10195214; 12588888; 15079006; 16685696; 18806275; 18252226; 20301347; 23108489; 25792100
Manifestations have been reported in heterozygotes

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the CHRNA1 gene.

• Lethal multiple pterygium syndrome (335 variants)
• not provided (126 variants)
• Congenital myasthenic syndrome (46 variants)
• not specified (19 variants)
• Inborn genetic diseases (18 variants)
• Congenital myasthenic syndrome 1A (11 variants)
• Myasthenic syndrome, congenital, 1B, fast-channel (7 variants)
• Autosomal recessive multiple pterygium syndrome (4 variants)
• Congenital Myasthenic Syndrome, Dominant/Recessive (4 variants)
• CHRNA1-related condition (3 variants)
• Myasthenic syndrome, slow-channel congenital (2 variants)
• Pleural effusion;Fetal ascites;Hydrops fetalis (1 variants)
• Epilepsy (1 variants)
• Myasthenic syndrome, congenital, 1B, fast-channel;Lethal multiple pterygium syndrome;Congenital myasthenic syndrome 1A (1 variants)
• Congenital myasthenic syndrome 1A;Lethal multiple pterygium syndrome;Myasthenic syndrome, congenital, 1B, fast-channel (1 variants)
• See cases (1 variants)
• Seizure;Autism (1 variants)
• Non-immune hydrops fetalis (1 variants)
• Seizure (1 variants)
• Juvenile myoclonic epilepsy (1 variants)
• CHRNA1-Related Congenital Myasthenic Syndrome (1 variants)
• Lethal multiple pterygium syndrome;Myasthenic syndrome, congenital, 1B, fast-channel;Congenital myasthenic syndrome 1A (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CHRNA1 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		2	4	67	1	74
missense	1	7	165	4	1	178
nonsense	4		1			5
start loss						0
frameshift	4	2	1			7
inframe indel			1			1
splice donor/acceptor (+/-2bp)	1	4				5
splice region			11	9	3	23
non coding			13	51	34	98
Total	10	15	185	122	36

Highest pathogenic variant AF is 0.0000195

Variants in CHRNA1

This is a list of pathogenic ClinVar variants found in the CHRNA1 region.

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

Position	Type	Phenotype	Significance	ClinVar
2-174747625-T-A		Lethal multiple pterygium syndrome • Congenital myasthenic syndrome	Conflicting classifications of pathogenicity (May 22, 2021)
2-174747658-C-G		Congenital myasthenic syndrome • Lethal multiple pterygium syndrome	Uncertain significance (Apr 27, 2017)
2-174747663-T-A		Lethal multiple pterygium syndrome • Congenital myasthenic syndrome	Uncertain significance (Jan 13, 2018)
2-174747698-G-T		Lethal multiple pterygium syndrome • Congenital myasthenic syndrome	Benign/Likely benign (Aug 31, 2021)
2-174747702-C-A		Lethal multiple pterygium syndrome • Congenital myasthenic syndrome	Conflicting classifications of pathogenicity (Jan 13, 2018)
2-174747710-A-T		Lethal multiple pterygium syndrome • Congenital myasthenic syndrome	Uncertain significance (Jan 12, 2018)
2-174747713-C-T		Lethal multiple pterygium syndrome • Congenital myasthenic syndrome	Conflicting classifications of pathogenicity (Jan 13, 2018)
2-174747741-A-G		Congenital myasthenic syndrome • Lethal multiple pterygium syndrome	Uncertain significance (Jan 13, 2018)
2-174747766-G-A		Congenital myasthenic syndrome • Lethal multiple pterygium syndrome	Uncertain significance (Jan 12, 2018)
2-174747814-G-A		Congenital myasthenic syndrome • Lethal multiple pterygium syndrome	Uncertain significance (Jan 12, 2018)
2-174747836-C-T		Congenital myasthenic syndrome • Lethal multiple pterygium syndrome	Uncertain significance (Jan 12, 2018)
2-174747849-T-C		Lethal multiple pterygium syndrome • Congenital myasthenic syndrome	Uncertain significance (Jan 13, 2018)
2-174747906-G-A		Congenital myasthenic syndrome • Lethal multiple pterygium syndrome	Benign/Likely benign (Nov 05, 2020)
2-174747994-T-A		Congenital myasthenic syndrome • Lethal multiple pterygium syndrome	Uncertain significance (Apr 28, 2017)
2-174748023-G-A		Congenital myasthenic syndrome • Lethal multiple pterygium syndrome	Uncertain significance (Jan 13, 2018)
2-174748150-G-A		Lethal multiple pterygium syndrome	Uncertain significance (Jul 14, 2023)
2-174748153-G-A		Lethal multiple pterygium syndrome	Uncertain significance (Aug 17, 2022)
2-174748155-C-T		Lethal multiple pterygium syndrome	Uncertain significance (Feb 08, 2022)
2-174748164-A-T		Lethal multiple pterygium syndrome	Uncertain significance (Jul 06, 2022)
2-174748165-C-T		Lethal multiple pterygium syndrome	Uncertain significance (Dec 02, 2022)
2-174748166-G-A		Congenital myasthenic syndrome • Lethal multiple pterygium syndrome	Conflicting classifications of pathogenicity (Apr 01, 2022)
2-174748169-T-A		Lethal multiple pterygium syndrome	Likely benign (Apr 06, 2022)
2-174748177-C-T		Lethal multiple pterygium syndrome • Seizure;Autism	Pathogenic/Likely pathogenic (Oct 06, 2023)
2-174748178-G-A		not specified • Lethal multiple pterygium syndrome	Likely benign (Aug 02, 2023)
2-174748179-A-G		CHRNA1-related disorder	Uncertain significance (Dec 15, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CHRNA1	protein_coding	protein_coding	ENST00000261007	10	16881

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
2.07e-8	0.683	125690	0	58	125748	0.000231

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.722	250	284	0.880	0.0000175	3181
Missense in Polyphen		85	109.75	0.77448		1235
Synonymous	-0.0812	113	112	1.01	0.00000775	939
Loss of Function	1.28	15	21.4	0.701	9.20e-7	251

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000421	0.000420
Ashkenazi Jewish	0.0000993	0.0000992
East Asian	0.000686	0.000653
Finnish	0.00	0.00
European (Non-Finnish)	0.000291	0.000281
Middle Eastern	0.000686	0.000653
South Asian	0.0000653	0.0000653
Other	0.000170	0.000163

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. {ECO:0000269|PubMed:27375219}.
• Disease: DISEASE: Note=The alpha subunit is the main focus for antibody binding in myasthenia gravis. Myasthenia gravis is characterized by sporadic muscular fatigability and weakness, occurring chiefly in muscles innervated by cranial nerves, and characteristically improved by cholinesterase-inhibiting drugs.; DISEASE: Myasthenic syndrome, congenital, 1A, slow-channel (CMS1A) [MIM:601462]: A common congenital myasthenic syndrome. Congenital myasthenic syndromes are characterized by muscle weakness affecting the axial and limb muscles (with hypotonia in early- onset forms), the ocular muscles (leading to ptosis and ophthalmoplegia), and the facial and bulbar musculature (affecting sucking and swallowing, and leading to dysphonia). The symptoms fluctuate and worsen with physical effort. CMS1A is a slow-channel myasthenic syndrome. It is caused by kinetic abnormalities of the AChR, resulting in prolonged AChR channel opening episodes, prolonged endplate currents, and depolarization block. This is associated with calcium overload, which may contribute to subsequent degeneration of the endplate and postsynaptic membrane. {ECO:0000269|PubMed:16685696, ECO:0000269|PubMed:7619526, ECO:0000269|PubMed:8872460, ECO:0000269|PubMed:9158151, ECO:0000269|PubMed:9221765}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Myasthenic syndrome, congenital, 1B, fast-channel (CMS1B) [MIM:608930]: A form of congenital myasthenic syndrome, a group of disorders characterized by failure of neuromuscular transmission, including pre-synaptic, synaptic, and post-synaptic disorders that are not of autoimmune origin. Clinical features are easy fatigability and muscle weakness affecting the axial and limb muscles (with hypotonia in early-onset forms), the ocular muscles (leading to ptosis and ophthalmoplegia), and the facial and bulbar musculature (affecting sucking and swallowing, and leading to dysphonia). The symptoms fluctuate and worsen with physical effort. CMS1B is a fast-channel myasthenic syndrome. It is caused by kinetic abnormalities of the AChR, resulting in brief opening and activity of the channel, with a rapid decay in endplate current, failure to achieve threshold depolarization of the endplate and consequent failure to fire an action potential. {ECO:0000269|PubMed:10195214, ECO:0000269|PubMed:12588888, ECO:0000269|PubMed:15079006}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Neuroactive ligand-receptor interaction - Homo sapiens (human);Effects of Botulinum toxin;Neuronal System;actions of nitric oxide in the heart;agrin in postsynaptic differentiation;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;ErbB2/ErbB3 signaling events (Consensus)

Recessive Scores

• pRec: 0.381

Intolerance Scores

• loftool: 0.163
• rvis_EVS: -0.33
• rvis_percentile_EVS: 30.7

Haploinsufficiency Scores

• pHI: 0.107
• hipred: N
• hipred_score: 0.309
• ghis: 0.455

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.734

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Chrna1
• Phenotype: 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); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); skeleton 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)

Zebrafish Information Network

• Gene name: chrna1
• Affected structure: Rohon-Beard neuron
• Phenotype tag: abnormal
• Phenotype quality: morphology

Gene ontology

• Biological process: skeletal muscle contraction;cation transport;signal transduction;chemical synaptic transmission;synaptic transmission, cholinergic;neuromuscular synaptic transmission;neuromuscular junction development;neuronal action potential;ion transmembrane transport;response to nicotine;regulation of membrane potential;muscle cell cellular homeostasis;skeletal muscle tissue growth;nervous system process;musculoskeletal movement;neuromuscular process;excitatory postsynaptic potential;neuron cellular homeostasis
• Cellular component: plasma membrane;integral component of plasma membrane;acetylcholine-gated channel complex;cell surface;cell junction;neuromuscular junction;neuron projection;synapse;postsynaptic membrane;integral component of postsynaptic specialization membrane
• Molecular function: ion channel activity;extracellular ligand-gated ion channel activity;acetylcholine receptor activity;acetylcholine-gated cation-selective channel activity;acetylcholine binding;transmitter-gated ion channel activity involved in regulation of postsynaptic membrane potential