2-232542806-G-C

Variant names:

• chr2-232542806-G-C
• rs2697782
• NM_005199.5:c.605-76G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005199.5(CHRNG):​c.605-76G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.333 in 1,337,110 control chromosomes in the GnomAD database, including 76,386 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (9993 hom., cov: 33)
  • Exomes 𝑓: 0.33 (66393 hom.)
• Consequence: CHRNG NM_005199.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.618
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-232542806-G-C is Benign according to our data. Variant chr2-232542806-G-C is described in ClinVar as Benign. ClinVar VariationId is 1271657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.435 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.605-76G>C		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.605-76G>C		intron	N/A	ENSP00000498757.1
	CHRNG	ENST00000389492.3	TSL:1	c.449-76G>C		intron	N/A	ENSP00000374143.3

Frequencies

GnomAD3 genomes AF: 0.355 AC: 54026 AN: 151984 Hom.: 9980 Cov.: 33

Gnomad AFR AF: 0.440

Gnomad AMI AF: 0.337

Gnomad AMR AF: 0.253

Gnomad ASJ AF: 0.304

Gnomad EAS AF: 0.342

Gnomad SAS AF: 0.243

Gnomad FIN AF: 0.363

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.339

Gnomad OTH AF: 0.315

GnomAD4 exome AF: 0.330 AC: 391622 AN: 1185008 Hom.: 66393 AF XY: 0.327 AC XY: 195594 AN XY: 597670

African (AFR) AF: 0.450 AC: 12636 AN: 28064

American (AMR) AF: 0.224 AC: 8426 AN: 37624

Ashkenazi Jewish (ASJ) AF: 0.298 AC: 7132 AN: 23914

East Asian (EAS) AF: 0.304 AC: 10972 AN: 36036

South Asian (SAS) AF: 0.239 AC: 18510 AN: 77304

European-Finnish (FIN) AF: 0.353 AC: 13592 AN: 38480

Middle Eastern (MID) AF: 0.290 AC: 1246 AN: 4292

European-Non Finnish (NFE) AF: 0.340 AC: 302288 AN: 887830

Other (OTH) AF: 0.327 AC: 16820 AN: 51464

GnomAD4 genome AF: 0.356 AC: 54078 AN: 152102 Hom.: 9993 Cov.: 33 AF XY: 0.352 AC XY: 26147 AN XY: 74340

African (AFR) AF: 0.441 AC: 18281 AN: 41482

American (AMR) AF: 0.252 AC: 3860 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.304 AC: 1057 AN: 3472

East Asian (EAS) AF: 0.342 AC: 1764 AN: 5158

South Asian (SAS) AF: 0.243 AC: 1174 AN: 4826

European-Finnish (FIN) AF: 0.363 AC: 3838 AN: 10578

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.339 AC: 23059 AN: 67978

Other (OTH) AF: 0.312 AC: 661 AN: 2116

Alfa AF: 0.156 Hom.: 312

Bravo AF: 0.352

Asia WGS AF: 0.263 AC: 912 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jul 31, 2019

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	-0.84
CADD	Benign	7.6
DANN	Benign	0.66
PhyloP100		0.62
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2697782; hg19: chr2-233407516; COSMIC: COSV67316144; COSMIC: COSV67316144;