2-232542288-T-G

Variant names:

• chr2-232542288-T-G
• rs1881492
• NM_005199.5:c.507-135T>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005199.5(CHRNG):​c.507-135T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.814 in 692,560 control chromosomes in the GnomAD database, including 230,215 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.81 (49908 hom., cov: 31)
  • Exomes 𝑓: 0.82 (180307 hom.)
• Consequence: CHRNG NM_005199.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.486
• Publications: 29 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-232542288-T-G is Benign according to our data. Variant chr2-232542288-T-G is described in ClinVar as Benign. ClinVar VariationId is 1246168.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.85 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNG	NM_005199.5	MANE Select	c.507-135T>G		intron	N/A	NP_005190.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNG	ENST00000651502.1	MANE Select	c.507-135T>G		intron	N/A	ENSP00000498757.1
	CHRNG	ENST00000389492.3	TSL:1	c.351-135T>G		intron	N/A	ENSP00000374143.3

Frequencies

GnomAD3 genomes AF: 0.809 AC: 122995 AN: 151984 Hom.: 49868 Cov.: 31

Gnomad AFR AF: 0.803

Gnomad AMI AF: 0.808

Gnomad AMR AF: 0.818

Gnomad ASJ AF: 0.887

Gnomad EAS AF: 0.871

Gnomad SAS AF: 0.841

Gnomad FIN AF: 0.796

Gnomad MID AF: 0.848

Gnomad NFE AF: 0.802

Gnomad OTH AF: 0.803

GnomAD4 exome AF: 0.816 AC: 440938 AN: 540458 Hom.: 180307 AF XY: 0.817 AC XY: 237408 AN XY: 290528

African (AFR) AF: 0.800 AC: 12489 AN: 15606

American (AMR) AF: 0.846 AC: 28521 AN: 33726

Ashkenazi Jewish (ASJ) AF: 0.882 AC: 16420 AN: 18616

East Asian (EAS) AF: 0.856 AC: 27321 AN: 31904

South Asian (SAS) AF: 0.832 AC: 48998 AN: 58914

European-Finnish (FIN) AF: 0.792 AC: 28150 AN: 35526

Middle Eastern (MID) AF: 0.814 AC: 2640 AN: 3242

European-Non Finnish (NFE) AF: 0.805 AC: 251915 AN: 313006

Other (OTH) AF: 0.818 AC: 24484 AN: 29918

GnomAD4 genome AF: 0.809 AC: 123091 AN: 152102 Hom.: 49908 Cov.: 31 AF XY: 0.811 AC XY: 60259 AN XY: 74342

African (AFR) AF: 0.803 AC: 33290 AN: 41468

American (AMR) AF: 0.818 AC: 12512 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.887 AC: 3079 AN: 3470

East Asian (EAS) AF: 0.872 AC: 4497 AN: 5160

South Asian (SAS) AF: 0.840 AC: 4052 AN: 4824

European-Finnish (FIN) AF: 0.796 AC: 8424 AN: 10580

Middle Eastern (MID) AF: 0.857 AC: 252 AN: 294

European-Non Finnish (NFE) AF: 0.802 AC: 54555 AN: 67998

Other (OTH) AF: 0.805 AC: 1693 AN: 2104

Alfa AF: 0.807 Hom.: 160019

Bravo AF: 0.812

Asia WGS AF: 0.861 AC: 2991 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.5
DANN	Benign	0.55
PhyloP100		-0.49
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1881492; hg19: chr2-233406998;