GeneBe

CHRNG

protein-coding

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

Gene summary

The mammalian muscle-type acetylcholine receptor is a transmembrane pentameric glycoprotein with two alpha subunits, one beta, one delta, and one epsilon (in adult skeletal muscle) or gamma (in fetal and denervated muscle) subunit. This gene, which encodes the gamma subunit, is expressed prior to the thirty-third week of gestation in humans. The gamma subunit of the acetylcholine receptor plays a role in neuromuscular organogenesis and ligand binding and disruption of gamma subunit expression prevents the correct localization of the receptor in cell membranes. Mutations in this gene cause Escobar syndrome and a lethal form of multiple pterygium syndrome. Muscle-type acetylcholine receptor is the major antigen in the autoimmune disease myasthenia gravis.[provided by RefSeq, Sep 2009]

Previous symbols:
  • ACHRG

MANE transcript

NM_005199.5

Inheritance

AR

ClinVar variants

P:85U:112B:174

Top phenotype

Multiple pterygium syndrome, lethal type; Escobar syndrome

gnomAD constraint

pLI —, LoF o/e 0.97

Max pathogenic AF

—

Genomic locus

chr2:232,539,692-232,548,115

External References & Databases

Ensembl (ENSG00000196811)NCBI Gene (1146)OMIM (100730)HGNC:1967GenCCUniProt (P07510)AlphaFoldClinVar (CHRNG)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~8.4 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

transient neonatal myasthenia gravisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0018326

Submitter: Genomics England PanelApp

lethal multiple pterygium syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009668

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive multiple pterygium syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009926

Submitter: Ambry Genetics

CHRNG-associated hypo-akinesia disorder of prenatal onsetDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100158

Submitter: ClinGen

Cholinergic Receptor, Nicotinic, Gamma Polypeptide (CHRNG; MIM#100730) is the gamma subunit of the Acetylcholine receptor (AChR). CHRNG is the variable subunit of AChR, which is present in humans before 33 weeks of gestational age and replaced by the 𝜀 subunit (CHRNE; MIM#100725) in late fetal and perinatal period. Fetal AChR is critical for establishing muscle-axon interface and neuromuscular junctions as well as prenatal neuromuscular signal transduction. Biallelic pathogenic variants in CHRNG are associated with CHRNG-associated hypo-akinesia disorder of prenatal onset (MONDO:0100158) with autosomal recessive inheritance pattern. Clinical phenotypes are variable include prenatal akinesia and associated resulting phenotypes, pterygium, poly- or oligohydramnios, intrauterine growth restriction, cystic hygroma, hydrops, reduced fetal movements, muscle weakness, congenital contractures, and fetal demise or stillbirth. The molecular etiology of CHRNG-associated disease was first reported by Hoffmann (2006; PMID:16826520) and Morgan (2006; PMID:16826531), and since has been reported in many additional male and female probands and found to segregate with disease in families and genetic evidence was scored at the maximum of 12 points [PMIDs:16826520, 16826531, 30868735, 34440395]. Functional evidence including expression studies [PMID:18252226, 16826520] and a mouse model recapitulating the observed human phenotype [PMID:12101101] were scored for an additional 3.0 points. Given this and its replication in the literature over time, the association of CHRNG with CHRNG-associated hypo-akinesia disorder of prenatal onset is curated as Definitive by the Prenatal Gene Curation Expert Panel.

lethal multiple pterygium syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009668

Submitter: Orphanet

autosomal recessive multiple pterygium syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009926

Submitter: Orphanet

autosomal recessive multiple pterygium syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009926

Submitter: G2P

Clinical Genomic Database (CGD)

Multiple pterygium syndrome, lethal type; Escobar syndromeAR

Manifestation: Craniofacial; Musculoskeletal

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: 16826520; 16826531; 22167768; 25608830Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CHRNG variants in ClinVar

19 Conditions Cataloged
not providedTotal: 391
Autosomal recessive multiple pterygium syndromeTotal: 99
Lethal multiple pterygium syndromeTotal: 98
Inborn genetic diseasesTotal: 93
CHRNG-related disorderTotal: 29
not specifiedTotal: 24
CHRNG-associated hypo-akinesia disorder of prenatal onsetTotal: 5
ScoliosisTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005199.5. 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.

EffectPLPVUSLBBSum
synonymous
2
clinvar
157
clinvar
 159
missense
2
clinvar
6
clinvar
109
clinvar
16
clinvar
1
clinvar
 134
nonsense
13
clinvar
12
clinvar
 25
start loss
1
clinvar
 1
frameshift
18
clinvar
12
clinvar
1
clinvar
 31
splice donor/acceptor (+/-2bp)
2
clinvar
19
clinvar
 21
Total35501121731371

Highest pathogenic variant AF is 0.0007217913

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 3 of 3 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_005199.5RefSeqNP_005190.412MANE Select
ENST00000651502.1EnsemblENSP00000498757.112MANE Select
ENST00000389492.3EnsemblENSP00000374143.311Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Neuroactive ligand-receptor interaction - Homo sapiens (human)
  • Highly sodium permeable acetylcholine nicotinic receptors
  • Neuronal System
  • role of nicotinic acetylcholine receptors in the regulation of apoptosis
  • Neurotransmitter receptors and postsynaptic signal transmission

Biological Process

  • muscle contraction
  • signal transduction
  • chemical synaptic transmission
  • synaptic transmission, cholinergic
  • neuromuscular synaptic transmission

Molecular Function

  • extracellular ligand-gated ion channel activity
  • protein binding
  • channel activity
  • acetylcholine receptor activity
  • acetylcholine-gated cation-selective channel activity

Cellular Component

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

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000389494
Coding exons
12
Length
6677
Individuals with no LoFs
125488
Homozygous LoFs
0
Heterozygous LoFs
260
Defined
125748
p
0.00103
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.1183103041.020.00002093325
Missense (PolyPhen)110121.310.90681437
Synonymous0.02801351350.9970.000009631101
Loss of Function0.1772930.00.9650.00000187275

Population LoF Frequency

PopulationCAFp-valueStatus
African0.00120.0012notable
Latino/Admixed American0.000870.00087rare
Ashkenazi Jewish0.000200.00020rare
East Asian0.000870.00087rare
Finnish0.000790.00079rare
European (Non-Finnish)0.00120.0012notable
South Asian0.00120.0010notable
Other0.00150.0015notable

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.;
Disease
DISEASE: Multiple pterygium syndrome, lethal type (LMPS) [MIM:253290]: Multiple pterygia are found infrequently in children with arthrogryposis and in fetuses with fetal akinesia syndrome. In lethal multiple pterygium syndrome there is intrauterine growth retardation, multiple pterygia, and flexion contractures causing severe arthrogryposis and fetal akinesia. Subcutaneous edema can be severe, causing fetal hydrops with cystic hygroma and lung hypoplasia. Oligohydramnios and facial anomalies are frequent. {ECO:0000269|PubMed:16826520, ECO:0000269|PubMed:16826531}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Multiple pterygium syndrome, Escobar variant (EVMPS) [MIM:265000]: Non-lethal form of arthrogryposis multiplex congenita. It is an autosomal recessive condition characterized by excessive webbing (pterygia), congenital contractures (arthrogryposis), and scoliosis. Variable other features include intrauterine death, congenital respiratory distress, short stature, faciocranial dysmorphism, ptosis, low-set ears, arachnodactyly and cryptorchism in males. Congenital contractures are common and may be caused by reduced fetal movements at sensitive times of development. Possible causes of decreased fetal mobility include space constraints such as oligohydramnion, drugs, metabolic conditions or neuromuscular disorders including myasthenia gravis. {ECO:0000269|PubMed:16826520, ECO:0000269|PubMed:16826531}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.0850

Intolerance Scores

LoFtool
0.308
RVIS EVS
-0.42
RVIS percentile EVS
25.79

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.616

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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