CHRNE

cholinergic receptor nicotinic epsilon subunit, the group of Cholinergic receptors nicotinic subunits

Basic information

Region (hg38): 17:4897770-4934438

Links

ENSG00000108556 ∙ NCBI:1145 ∙ OMIM:100725 ∙ HGNC:1966 ∙ Uniprot:Q04844 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• congenital myasthenic syndrome (Definitive), mode of inheritance: AR
• congenital myasthenic syndrome 4A (Strong), mode of inheritance: AD
• congenital myasthenic syndrome 4A (Strong), mode of inheritance: AR
• congenital myasthenic syndrome 4B (Strong), mode of inheritance: AR
• congenital myasthenic syndrome 4C (Strong), mode of inheritance: AR
• congenital myasthenic syndrome 4A (Strong), mode of inheritance: AD
• congenital myasthenic syndrome 4B (Strong), mode of inheritance: AR
• postsynaptic congenital myasthenic syndrome (Supportive), mode of inheritance: AR
• congenital myasthenic syndrome 4A (Strong), mode of inheritance: AD
• congenital myasthenic syndrome 4B (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Myasthenic syndrome, congenital, 4A, slow-channel; Myasthenic syndrome, congenital, 4B, fast-channel; Myasthenic syndrome, congenital, 4C, associated with acetylcholine receptor deficiency	AD/AR	Musculoskeletal; Neurologic; Pharmacogenomic	Most individuals with Myasthenic syndrome, congenital, 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	8232384; 7538206; 7531341; 8957026; 8872460; 8755487; 9158150; 0514102; 10211467; 10962020; 10534268; 11030414; 12141316; 12034803; 15322984; 16087917; 19064877; 20301347; 20562457; 23108489; 25792100

ClinVar

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

• Congenital myasthenic syndrome 4A (928 variants)
• not provided (229 variants)
• Congenital myasthenic syndrome (209 variants)
• not specified (77 variants)
• Inborn genetic diseases (64 variants)
• Congenital myasthenic syndrome 4C (30 variants)
• Congenital myasthenic syndrome 4B (27 variants)
• Bernard-Soulier syndrome, type A2, autosomal dominant (22 variants)
• Congenital myasthenic syndrome 4A;Congenital myasthenic syndrome 4C;Congenital myasthenic syndrome 4B (17 variants)
• Bernard Soulier syndrome (13 variants)
• GP1BA-related condition (9 variants)
• Abnormality of the musculature (8 variants)
• Congenital myasthenic syndrome 4B;Congenital myasthenic syndrome 4A;Congenital myasthenic syndrome 4C (8 variants)
• Pseudo von Willebrand disease (8 variants)
• Congenital Myasthenic Syndrome, Dominant/Recessive (7 variants)
• Macrothrombocytopenia (7 variants)
• Thrombocytopenia (6 variants)
• CHRNE-related condition (6 variants)
• Tip-toe gait (3 variants)
• Bernard-Soulier syndrome, type A1 (3 variants)
• See cases (2 variants)
• Thrombocytopenia;Abnormal bleeding (2 variants)
• Pseudo von Willebrand disease;Bernard Soulier syndrome;Bernard-Soulier syndrome, type A2, autosomal dominant (1 variants)
• CIC-DUX Sarcoma (1 variants)
• Congenital myasthenic syndrome 4C;Congenital myasthenic syndrome 4A;Congenital myasthenic syndrome 4B (1 variants)
• Bernard Soulier syndrome;Bernard-Soulier syndrome, type A2, autosomal dominant;Nonarteritic anterior ischemic optic neuropathy, susceptibility to;Pseudo von Willebrand disease (1 variants)
• Myasthenic syndrome, congenital, 1B, fast-channel (1 variants)
• Pseudo von Willebrand disease;Bernard Soulier syndrome;Bernard-Soulier syndrome, type A2, autosomal dominant;Nonarteritic anterior ischemic optic neuropathy, susceptibility to (1 variants)
• Pseudo von Willebrand disease;Bernard-Soulier syndrome, type A2, autosomal dominant;Bernard Soulier syndrome;Nonarteritic anterior ischemic optic neuropathy, susceptibility to (1 variants)
• Myasthenic syndrome, slow-channel congenital (1 variants)
• Multifocal seizures;Neurodevelopmental delay (1 variants)
• Impaired ristocetin-induced platelet aggregation (1 variants)
• CHRNE-related disorder (1 variants)
• Congenital myasthenic syndrome 4C;Congenital myasthenic syndrome 4B;Congenital myasthenic syndrome 4A (1 variants)
• Congenital myasthenic syndrome 1A (1 variants)
• Nonarteritic anterior ischemic optic neuropathy, susceptibility to;Bernard-Soulier syndrome, type A2, autosomal dominant;Pseudo von Willebrand disease;Bernard Soulier syndrome (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CHRNE 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	299	6	312
missense	7	23	243	6	2	281
nonsense	19	12	3			34
start loss		1				1
frameshift	63	39	2			104
inframe indel	1	4	11			16
splice donor/acceptor (+/-2bp)	8	22	1			31
splice region			12	59	4	75
non coding	15	22	92	115	39	283
Total	113	123	359	420	47

Highest pathogenic variant AF is 0.000290

Variants in CHRNE

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

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

Position	Type	Phenotype	Significance	ClinVar
17-4897806-A-C		Congenital myasthenic syndrome	Benign (Jan 13, 2018)
17-4897830-C-G		Congenital myasthenic syndrome	Benign (Jan 12, 2018)
17-4897833-C-T		Congenital myasthenic syndrome	Uncertain significance (Jan 13, 2018)
17-4897834-G-A		Congenital myasthenic syndrome	Uncertain significance (Jan 13, 2018)
17-4897860-C-T		Congenital myasthenic syndrome	Uncertain significance (Jan 13, 2018)
17-4897861-G-A		Congenital myasthenic syndrome	Uncertain significance (Jan 12, 2018)
17-4897868-C-A		Congenital myasthenic syndrome	Benign (Jan 12, 2018)
17-4897878-C-G		Congenital myasthenic syndrome	Likely benign (Jan 13, 2018)
17-4897881-G-A		Congenital myasthenic syndrome	Uncertain significance (Apr 27, 2017)
17-4897884-C-T		Congenital myasthenic syndrome	Uncertain significance (Jan 13, 2018)
17-4897899-T-C		Congenital myasthenic syndrome	Benign (Jan 13, 2018)
17-4897900-G-A		Congenital myasthenic syndrome	Uncertain significance (Jan 13, 2018)
17-4897930-C-T		Congenital myasthenic syndrome	Uncertain significance (Jan 12, 2018)
17-4897931-A-C		Congenital myasthenic syndrome	Uncertain significance (Jan 13, 2018)
17-4897956-A-AGT		Congenital Myasthenic Syndrome, Dominant/Recessive	Uncertain significance (Jun 14, 2016)
17-4897978-TCTCC-T		Congenital Myasthenic Syndrome, Dominant/Recessive	Uncertain significance (Jun 14, 2016)
17-4897988-C-T		Congenital myasthenic syndrome	Benign (Jan 13, 2018)
17-4897991-C-T		Congenital myasthenic syndrome	Benign (Jan 12, 2018)
17-4897991-C-CT		Congenital Myasthenic Syndrome, Dominant/Recessive	Uncertain significance (Jun 14, 2016)
17-4897993-A-C		Congenital myasthenic syndrome	Benign (Jan 13, 2018)
17-4898114-G-A		Congenital myasthenic syndrome	Uncertain significance (Jan 13, 2018)
17-4898126-G-A		Congenital myasthenic syndrome	Benign (Jan 13, 2018)
17-4898139-C-T		Congenital myasthenic syndrome	Uncertain significance (Jan 12, 2018)
17-4898146-G-A		Congenital myasthenic syndrome	Uncertain significance (Jan 13, 2018)
17-4898164-G-C		Congenital myasthenic syndrome	Uncertain significance (Jan 13, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CHRNE	protein_coding	protein_coding	ENST00000293780	12	5301

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
4.73e-9	0.827	125611	0	137	125748	0.000545

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.850	359	316	1.13	0.0000225	3127
Missense in Polyphen		154	140.53	1.0959		1444
Synonymous	-2.92	188	144	1.31	0.0000118	1013
Loss of Function	1.60	17	25.8	0.660	0.00000142	259

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00162	0.00159
Ashkenazi Jewish	0.00325	0.00298
East Asian	0.000349	0.000326
Finnish	0.0000553	0.0000462
European (Non-Finnish)	0.000354	0.000334
Middle Eastern	0.000349	0.000326
South Asian	0.000431	0.000425
Other	0.000833	0.000815

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 muscle AChR is the major target antigen in the autoimmune disease 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, 4A, slow-channel (CMS4A) [MIM:605809]: 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. CMS4A 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:12141316, ECO:0000269|PubMed:27375219, ECO:0000269|PubMed:7531341, ECO:0000269|PubMed:7538206, ECO:0000269|PubMed:8872460}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Myasthenic syndrome, congenital, 4B, fast-channel (CMS4B) [MIM:616324]: 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. CMS4B 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:10962020, ECO:0000269|PubMed:22592360, ECO:0000269|PubMed:8755487}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Myasthenic syndrome, congenital, 4C, associated with acetylcholine receptor deficiency (CMS4C) [MIM:608931]: 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. CMS4C is an autosomal recessive disorder of postsynaptic neuromuscular transmission, due to deficiency of AChR at the endplate that results in low amplitude of the miniature endplate potential and current. {ECO:0000269|PubMed:9158150}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Neuroactive ligand-receptor interaction - Homo sapiens (human);Highly sodium permeable acetylcholine nicotinic receptors;Neuronal System;Neurotransmitter receptors and postsynaptic signal transmission;Transmission across Chemical Synapses;Presynaptic 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: 0.100

Intolerance Scores

• loftool: 0.160
• rvis_EVS: -0.91
• rvis_percentile_EVS: 10.03

Haploinsufficiency Scores

• pHI: 0.510
• hipred: N
• hipred_score: 0.414
• ghis: 0.537

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.710

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Chrne
• Phenotype: growth/size/body region phenotype; muscle 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); respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); 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: chrne
• Affected structure: synaptic transmission, cholinergic
• Phenotype tag: abnormal
• Phenotype quality: amplitude

Gene ontology

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