CHRNB4

protein-coding

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

Gene summary

This gene is found within a conserved gene cluster and encodes one of the beta subunits of the nicotinic acetylcholine receptor (nAChRs) superfamily which form ligand-gated ion channels with a central pore that forms a cation channel. Neuronal nAChRs are pentameric structures that can be either homomeric or heteromeric, with heteromeric structures containing both alpha and beta subunits. Each subunit contains an extracellular amino terminus and four transmembrane domains. Nicotine is one of the agonists that binds to the receptor. Variants in this gene have been associated with nicotine dependence and lung cancer. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Sep 2017]

MANE transcript

NM_000750.5

Inheritance

ClinVar variants

P:2U:45B:16

Top phenotype

Amyotrophic lateral sclerosis

gnomAD constraint

pLI —, LoF o/e 0.27

Max pathogenic AF

—

Genomic locus

chr15:78,624,111-78,727,754

External References & Databases

Ensembl (ENSG00000117971)

Transcript & Mutation Effects

hg38 • Region Span ~103.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

lung cancerLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0008903

Submitter: Ambry Genetics

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CHRNB4 variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 46

not providedTotal: 8

Amyotrophic lateral sclerosisTotal: 3

Frontotemporal dementiaTotal: 2

EBV-positive nodal T- and NK-cell lymphomaTotal: 1

Chronic obstructive pulmonary diseaseTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000750.5. 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				3 clinvar	3 clinvar	6
missense		2 clinvar	44 clinvar	6 clinvar	4 clinvar	56
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	2	45	9	7	63

Highest pathogenic variant AF is 0.00003717509

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 21 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000750.5	RefSeq	NP_000741.1	6	MANE Select
ENST00000261751.8	Ensembl	ENSP00000261751.3	6	MANE Select
NM_001256567.3	RefSeq	NP_001243496.1	5	Standard
ENST00000412074.6	Ensembl	ENSP00000416386.2	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Neuroactive ligand-receptor interaction - Homo sapiens (human)
Cholinergic synapse - Homo sapiens (human)
Nicotine Pathway (Chromaffin Cell), Pharmacodynamics
Nicotine Activity on Chromaffin Cells
Sudden Infant Death Syndrome (SIDS) Susceptibility Pathways

Biological Process

action potential
ion transport
smooth muscle contraction
regulation of smooth muscle contraction
signal transduction

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
integral component of membrane
cell junction

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000261751
Coding exons: 6
Length: 103636
Individuals with no LoFs: 125729
Homozygous LoFs: 0
Heterozygous LoFs: 19
Defined: 125748
p: 0.0000756

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.20	257	317	0.811	0.0000200	3246
Missense (PolyPhen)		107	150.54	0.71078		1653
Synonymous	-1.01	152	137	1.11	0.00000957	1029
Loss of Function	2.95	5	18.8	0.266	9.76e-7	190

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00014	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000097	0.000097	rare
South Asian	0.000065	0.000065	rare
Other	0.00033	0.00033	rare

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.;

Recessive Scores

pRec: 0.138

Intolerance Scores

LoFtool: 0.144
RVIS EVS: 0.73
RVIS percentile EVS: 86.3

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.154

Gene Damage Prediction

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