CHRNA7

protein-coding

cholinergic receptor nicotinic alpha 7 subunit, the group of Cholinergic receptors nicotinic subunits

Gene summary

The nicotinic acetylcholine receptors (nAChRs) are members of a superfamily of ligand-gated ion channels that mediate fast signal transmission at synapses. The nAChRs are thought to be hetero-pentamers composed of homologous subunits. The proposed structure for each subunit is a conserved N-terminal extracellular domain followed by three conserved transmembrane domains, a variable cytoplasmic loop, a fourth conserved transmembrane domain, and a short C-terminal extracellular region. The protein encoded by this gene forms a homo-oligomeric channel, displays marked permeability to calcium ions and is a major component of brain nicotinic receptors that are blocked by, and highly sensitive to, alpha-bungarotoxin. Once this receptor binds acetylcholine, it undergoes an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. This gene is located in a region identified as a major susceptibility locus for juvenile myoclonic epilepsy and a chromosomal location involved in the genetic transmission of schizophrenia. An evolutionarily recent partial duplication event in this region results in a hybrid containing sequence from this gene and a novel FAM7A gene. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2012]

MANE transcript

NM_000746.6

Inheritance

ClinVar variants

U:80B:25

Top phenotype

Neurocognitive dysfunction with distinctive craniofacial features

gnomAD constraint

pLI —, LoF o/e 0.44

Max pathogenic AF

—

Genomic locus

chr15:31,923,438-32,173,018

External References & Databases

Ensembl (ENSG00000175344)

Transcript & Mutation Effects

hg38 • Region Span ~249.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complex neurodevelopmental disorderLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: Ambry Genetics

epilepsyNO_KNOWN

Inheritance Pattern: Unknown

Disease ID:MONDO:0005027

Submitter: ClinGen

*CHRNA7* was first reported as a candidate gene for autosomal dominant epilepsy (MONDO:0005027) in 2002 (PMID: 12049804) due to its presence within recurrent 15q13.3 copy number variants, which have been reported to increase the risk of idiopathic generalized epilepsy (PMID:19136953). Since this publication, most reported probands have had microdeletions and microduplications in the 15q13.3 region, which often includes at least six other genes (ARHGAP11B, MTMR15, MTMR10, TRPM1, KLF13, and OTUD7A). Because these deletions are not isolated to CHRNA7 alone, they are not included in this curation. Three missense variants that have been reported in three probands in one paper were evaluated as a part of this curation (PMID: 26421493). However, none of these cases were awarded points, as their variants were either inherited from a healthy parent, or were predicted to be benign. Another paper with a homozygous *CHRNA7* knock-out mouse model found no evidence of recapitulating phenotypes observed in humans, and there were no electrophysiological phenotypic differences between the wild type and knock-out mice (PMID: 28045139). Taken together, the evidence supporting the relationship between *CHRNA7* and autosomal dominant epilepsy has been REFUTED and no valid evidence remains to support the claim. This classification has been approved by the ClinGen Epilepsy GCEP on February 7th, 2023 (SOP Version 9).

Clinical Genomic Database (CGD)

Neurocognitive dysfunction with distinctive craniofacial featuresAD

Manifestation: Craniofacial; 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

Refs: 22775350

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CHRNA7 variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 85

not providedTotal: 32

CHRNA7-related disorderTotal: 4

Chromosome 15q13.3 microdeletion syndromeTotal: 1

Epilepsy, idiopathic generalized, susceptibility to, 7Total: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000746.6. 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				19 clinvar	1 clinvar	20
missense			75 clinvar	4 clinvar	1 clinvar	80
nonsense			2 clinvar			2
start loss			1 clinvar			1
frameshift						0
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	0	0	80	23	2	105

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 41 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000746.6	RefSeq	NP_000737.1	10	MANE Select
ENST00000306901.9	Ensembl	ENSP00000303727.2	10	MANE Select
NM_001190455.3	RefSeq	NP_001177384.1	10	Standard
ENST00000437966.3	Ensembl	ENSP00000399087.3	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Nicotine addiction - Homo sapiens (human)
Calcium signaling pathway - Homo sapiens (human)
Chemical carcinogenesis - Homo sapiens (human)
Neuroactive ligand-receptor interaction - Homo sapiens (human)
Cholinergic synapse - Homo sapiens (human)

Biological Process

activation of MAPK activity
response to hypoxia
positive regulation of protein phosphorylation
ion transport
calcium ion transport

Molecular Function

amyloid-beta binding
transmembrane signaling receptor activity
ion channel activity
extracellular ligand-gated ion channel activity
calcium channel activity

Cellular Component

plasma membrane
integral component of plasma membrane
acetylcholine-gated channel complex
integral component of membrane
cell junction

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000454250
Coding exons: 10
Length: 142032
Individuals with no LoFs: 125714
Homozygous LoFs: 0
Heterozygous LoFs: 34
Defined: 125748
p: 0.000135

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.25	190	245	0.776	0.0000139	3347
Missense (PolyPhen)		51	88.223	0.57808		1264
Synonymous	0.706	98	107	0.913	0.00000701	1010
Loss of Function	2.34	9	20.4	0.440	9.48e-7	266

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00026	0.00025	rare
Latino/Admixed American	0.00030	0.00029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.00017	0.00017	rare
South Asian	0.000034	0.000033	rare
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. The channel is blocked by alpha-bungarotoxin.;

Recessive Scores

pRec: 0.345

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.792

Gene Damage Prediction

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