2-232543615-C-A

Position:

chr2-232543615-C-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2

The NM_005199.5(CHRNG):c.951C>A(p.Ile317Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,613,384 control chromosomes in the GnomAD database, including 175 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.010 ( 23 hom., cov: 32)

Exomes 𝑓: 0.010 ( 152 hom. )

Consequence

CHRNG
NM_005199.5 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 0.0590

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.37).

BP6

Variant 2-232543615-C-A is Benign according to our data. Variant chr2-232543615-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 199105.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=4}. Variant chr2-232543615-C-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.059 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0102 (1554/152274) while in subpopulation EAS AF= 0.0346 (179/5170). AF 95% confidence interval is 0.0305. There are 23 homozygotes in gnomad4. There are 811 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNG	NM_005199.5 linkuse as main transcript	c.951C>A	p.Ile317Ile	synonymous_variant	9/12	ENST00000651502.1	NP_005190.4	P07510-1A0A6F7YAP6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNG	ENST00000651502.1 linkuse as main transcript	c.951C>A	p.Ile317Ile	synonymous_variant	9/12		NM_005199.5	ENSP00000498757.1		P07510-1
CHRNG	ENST00000389492.3 linkuse as main transcript	c.795C>A	p.Ile265Ile	synonymous_variant	8/11	1		ENSP00000374143.3		P07510-2

Frequencies

GnomAD3 genomes

AF:

0.0102

AC:

1555

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00150

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0232

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.0351

Gnomad SAS

AF:

0.00477

Gnomad FIN

AF:

0.0252

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00936

Gnomad OTH

AF:

0.0120

GnomAD3 exomes

AF:

0.0140

AC:

3522

AN:

251350

Hom.:

AF XY:

0.0125

AC XY:

1700

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.0343

Gnomad ASJ exome

AF:

0.00109

Gnomad EAS exome

AF:

0.0285

Gnomad SAS exome

AF:

0.00386

Gnomad FIN exome

AF:

0.0255

Gnomad NFE exome

AF:

0.00902

Gnomad OTH exome

AF:

0.0140

GnomAD4 exome

AF:

0.0101

AC:

14780

AN:

1461110

Hom.:

152

Cov.:

AF XY:

0.00987

AC XY:

7177

AN XY:

726898

show subpopulations

Gnomad4 AFR exome

AF:

0.000986

Gnomad4 AMR exome

AF:

0.0338

Gnomad4 ASJ exome

AF:

0.00107

Gnomad4 EAS exome

AF:

0.0360

Gnomad4 SAS exome

AF:

0.00435

Gnomad4 FIN exome

AF:

0.0254

Gnomad4 NFE exome

AF:

0.00844

Gnomad4 OTH exome

AF:

0.0107

GnomAD4 genome

AF:

0.0102

AC:

1554

AN:

152274

Hom.:

Cov.:

AF XY:

0.0109

AC XY:

811

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.00149

Gnomad4 AMR

AF:

0.0231

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.0346

Gnomad4 SAS

AF:

0.00519

Gnomad4 FIN

AF:

0.0252

Gnomad4 NFE

AF:

0.00936

Gnomad4 OTH

AF:

0.0118

Alfa

AF:

0.00844

Hom.:

Bravo

AF:

0.0107

Asia WGS

AF:

0.0230

AC:

AN:

3478

EpiCase

AF:

0.00851

EpiControl

AF:

0.00777

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 10, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 12, 2021	- -

Autosomal recessive multiple pterygium syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Lethal multiple pterygium syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.37

CADD

Benign

9.1

DANN

Benign

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over