rs2289080

Positions:

chr2-232541468-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005199.5(CHRNG):c.445G>A(p.Ala149Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0243 in 1,614,044 control chromosomes in the GnomAD database, including 865 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.028 ( 103 hom., cov: 32)

Exomes 𝑓: 0.024 ( 762 hom. )

Consequence

CHRNG
NM_005199.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.0180

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0039532185).

BP6

Variant 2-232541468-G-A is Benign according to our data. Variant chr2-232541468-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 259667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-232541468-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.1 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNG	NM_005199.5 linkuse as main transcript	c.445G>A	p.Ala149Thr	missense_variant	5/12	ENST00000651502.1	NP_005190.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNG	ENST00000651502.1 linkuse as main transcript	c.445G>A	p.Ala149Thr	missense_variant	5/12		NM_005199.5	ENSP00000498757	P1	P07510-1
CHRNG	ENST00000389492.3 linkuse as main transcript	c.350+757G>A		intron_variant		1		ENSP00000374143		P07510-2
CHRNG	ENST00000485094.1 linkuse as main transcript	n.466G>A		non_coding_transcript_exon_variant	5/5	1

Frequencies

GnomAD3 genomes

AF:

0.0278

AC:

4227

AN:

152134

Hom.:

103

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0283

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0438

Gnomad ASJ

AF:

0.00519

Gnomad EAS

AF:

0.108

Gnomad SAS

AF:

0.0292

Gnomad FIN

AF:

0.0332

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0182

Gnomad OTH

AF:

0.0325

GnomAD3 exomes

AF:

0.0335

AC:

8415

AN:

251456

Hom.:

229

AF XY:

0.0312

AC XY:

4240

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.0274

Gnomad AMR exome

AF:

0.0688

Gnomad ASJ exome

AF:

0.00754

Gnomad EAS exome

AF:

0.0887

Gnomad SAS exome

AF:

0.0276

Gnomad FIN exome

AF:

0.0336

Gnomad NFE exome

AF:

0.0187

Gnomad OTH exome

AF:

0.0303

GnomAD4 exome

AF:

0.0239

AC:

34990

AN:

1461792

Hom.:

762

Cov.:

AF XY:

0.0239

AC XY:

17368

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.0272

Gnomad4 AMR exome

AF:

0.0658

Gnomad4 ASJ exome

AF:

0.00708

Gnomad4 EAS exome

AF:

0.114

Gnomad4 SAS exome

AF:

0.0290

Gnomad4 FIN exome

AF:

0.0331

Gnomad4 NFE exome

AF:

0.0182

Gnomad4 OTH exome

AF:

0.0291

GnomAD4 genome

AF:

0.0279

AC:

4244

AN:

152252

Hom.:

103

Cov.:

AF XY:

0.0285

AC XY:

2121

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.0286

Gnomad4 AMR

AF:

0.0439

Gnomad4 ASJ

AF:

0.00519

Gnomad4 EAS

AF:

0.108

Gnomad4 SAS

AF:

0.0299

Gnomad4 FIN

AF:

0.0332

Gnomad4 NFE

AF:

0.0182

Gnomad4 OTH

AF:

0.0326

Alfa

AF:

0.0214

Hom.:

109

Bravo

AF:

0.0298

TwinsUK

AF:

0.0186

AC:

ALSPAC

AF:

0.0192

AC:

ESP6500AA

AF:

0.0229

AC:

101

ESP6500EA

AF:

0.0155

AC:

133

ExAC

AF:

0.0320

AC:

3885

Asia WGS

AF:

0.0540

AC:

189

AN:

3478

EpiCase

AF:

0.0170

EpiControl

AF:

0.0166

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 25, 2019	- -

Autosomal recessive multiple pterygium syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Congenital Myasthenic Syndrome, Dominant/Recessive

Benign:1

Likely benign, 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

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.52

CADD

Benign

9.3

DANN

Benign

0.96

DEOGEN2

Benign

0.13

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.76

MetaRNN

Benign

0.0040

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.29

MutationTaster

Benign

1.0

D;N;N

PrimateAI

Benign

0.31

PROVEAN

Benign

0.27

REVEL

Benign

0.18

Sift

Benign

0.37

Sift4G

Benign

0.44

Polyphen

0.010

Vest4

0.033

MPC

0.19

ClinPred

0.0099

GERP RS

2.3

Varity_R

0.099

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

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