chr2-232539760-C-A

Variant names:

• chr2-232539760-C-A
• rs267606725
• NM_005199.5:c.13C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005199.5(CHRNG):​c.13C>A​(p.Gln5Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CHRNG NM_005199.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.259
• Publications: 0 publications found

Genes affected

CHRNG (HGNC:1967): (cholinergic receptor nicotinic gamma subunit) 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]

CHRNG Gene-Disease associations (from GenCC):

• autosomal recessive multiple pterygium syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Orphanet
• CHRNG-associated hypo-akinesia disorder of prenatal onset

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet
• transient neonatal myasthenia gravis

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13715309).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005199.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNG	NM_005199.5	MANE Select	c.13C>A	p.Gln5Lys	missense	Exon 1 of 12	NP_005190.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNG	ENST00000651502.1	MANE Select	c.13C>A	p.Gln5Lys	missense	Exon 1 of 12	ENSP00000498757.1
	CHRNG	ENST00000389492.3	TSL:1	c.13C>A	p.Gln5Lys	missense	Exon 1 of 11	ENSP00000374143.3
	CHRNG	ENST00000485094.1	TSL:1	n.34C>A		non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461626 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727114

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53286

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111986

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	12
DANN	Benign	0.92
DEOGEN2	Benign	0.035	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.26
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.24
Sift	Benign	0.34	T
Sift4G	Benign	0.89	T
Polyphen		0.71	P
Vest4		0.30
MutPred		0.42		Gain of glycosylation at Q5 (P = 0.016)
MVP		0.60
MPC		0.18
ClinPred		0.20	T
GERP RS		1.7
PromoterAI		-0.0096	Neutral
Varity_R		0.14
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs267606725; hg19: chr2-233404470;