chr2-232543529-C-G

Variant names:

• chr2-232543529-C-G
• rs2573206
• NM_005199.5:c.921-56C>G

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.921-56C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.835 in 1,310,424 control chromosomes in the GnomAD database, including 457,526 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.83 (52915 hom., cov: 29)
  • Exomes 𝑓: 0.83 (404611 hom.)
• Consequence: CHRNG NM_005199.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.222
• Publications: 11 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=-0.89).
• BP6: Variant 2-232543529-C-G is Benign according to our data. Variant chr2-232543529-C-G is described in ClinVar as Benign. ClinVar VariationId is 1282133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.95 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNG	NM_005199.5	MANE Select	c.921-56C>G		intron	N/A	NP_005190.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNG	ENST00000651502.1	MANE Select	c.921-56C>G		intron	N/A	ENSP00000498757.1
	CHRNG	ENST00000389492.3	TSL:1	c.765-56C>G		intron	N/A	ENSP00000374143.3

Frequencies

GnomAD3 genomes AF: 0.834 AC: 126467 AN: 151714 Hom.: 52869 Cov.: 29

Gnomad AFR AF: 0.821

Gnomad AMI AF: 0.811

Gnomad AMR AF: 0.863

Gnomad ASJ AF: 0.893

Gnomad EAS AF: 0.973

Gnomad SAS AF: 0.870

Gnomad FIN AF: 0.827

Gnomad MID AF: 0.858

Gnomad NFE AF: 0.820

Gnomad OTH AF: 0.832

GnomAD4 exome AF: 0.835 AC: 967246 AN: 1158592 Hom.: 404611 Cov.: 16 AF XY: 0.836 AC XY: 492267 AN XY: 589058

African (AFR) AF: 0.823 AC: 22643 AN: 27520

American (AMR) AF: 0.913 AC: 38517 AN: 42168

Ashkenazi Jewish (ASJ) AF: 0.892 AC: 21467 AN: 24064

East Asian (EAS) AF: 0.965 AC: 36669 AN: 38014

South Asian (SAS) AF: 0.860 AC: 67917 AN: 78932

European-Finnish (FIN) AF: 0.822 AC: 42602 AN: 51798

Middle Eastern (MID) AF: 0.838 AC: 4357 AN: 5202

European-Non Finnish (NFE) AF: 0.822 AC: 690585 AN: 840624

Other (OTH) AF: 0.845 AC: 42489 AN: 50270

GnomAD4 genome AF: 0.834 AC: 126570 AN: 151832 Hom.: 52915 Cov.: 29 AF XY: 0.835 AC XY: 61984 AN XY: 74198

African (AFR) AF: 0.821 AC: 33989 AN: 41390

American (AMR) AF: 0.863 AC: 13183 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.893 AC: 3097 AN: 3470

East Asian (EAS) AF: 0.973 AC: 4981 AN: 5120

South Asian (SAS) AF: 0.869 AC: 4183 AN: 4812

European-Finnish (FIN) AF: 0.827 AC: 8717 AN: 10536

Middle Eastern (MID) AF: 0.867 AC: 255 AN: 294

European-Non Finnish (NFE) AF: 0.820 AC: 55666 AN: 67918

Other (OTH) AF: 0.833 AC: 1759 AN: 2112

Alfa AF: 0.825 Hom.: 6457

Bravo AF: 0.838

Asia WGS AF: 0.906 AC: 3149 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.6
DANN	Benign	0.76
PhyloP100		-0.22
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: rs2573206; hg19: chr2-233408239;