2-232540061-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_005199.5(CHRNG):c.125G>A(p.Arg42Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00287 in 1,614,220 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R42W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0025 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0029 ( 7 hom. )

Consequence

CHRNG
NM_005199.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: 7.76

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive multiple pterygium syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, 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: Labcorp Genetics (formerly Invitae), Orphanet
transient neonatal myasthenia gravis
Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp

CHRNG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10330105).

BP6

Variant 2-232540061-G-A is Benign according to our data. Variant chr2-232540061-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 376837.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00252 (384/152344) while in subpopulation NFE AF = 0.00422 (287/68022). AF 95% confidence interval is 0.00382. There are 4 homozygotes in GnomAd4. There are 187 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

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.125G>A	p.Arg42Gln	missense	Exon 2 of 12	NP_005190.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHRNG	ENST00000651502.1	MANE Select	c.125G>A	p.Arg42Gln	missense	Exon 2 of 12	ENSP00000498757.1	P07510-1
CHRNG	ENST00000389492.3	TSL:1	c.125G>A	p.Arg42Gln	missense	Exon 2 of 11	ENSP00000374143.3	P07510-2
CHRNG	ENST00000485094.1	TSL:1	n.146G>A		non_coding_transcript_exon	Exon 2 of 5

Frequencies

GnomAD3 genomes

AF:

0.00254

AC:

386

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000458

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00262

Gnomad ASJ

AF:

0.00691

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000847

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00423

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.00229

AC:

576

AN:

251312

AF XY:

0.00209

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.00188

Gnomad ASJ exome

AF:

0.00506

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.000647

Gnomad NFE exome

AF:

0.00374

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00291

AC:

4251

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00278

AC XY:

2023

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.000448

AC:

AN:

33480

American (AMR)

AF:

0.00203

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00528

AC:

138

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000468

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00340

AC:

3785

AN:

1112000

Other (OTH)

AF:

0.00320

AC:

193

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

287

574

860

1147

1434

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

134

268

402

536

670

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00252

AC:

384

AN:

152344

Hom.:

Cov.:

AF XY:

0.00251

AC XY:

187

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.000457

AC:

AN:

41580

American (AMR)

AF:

0.00261

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00691

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000847

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00422

AC:

287

AN:

68022

Other (OTH)

AF:

0.00190

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00312

Hom.:

Bravo

AF:

0.00240

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00326

AC:

ExAC

AF:

0.00247

AC:

300

EpiCase

AF:

0.00354

EpiControl

AF:

0.00391

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

not specified (2)

Autosomal recessive multiple pterygium syndrome (1)

CHRNG-related disorder (1)

Lethal multiple pterygium syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Benign

-0.028

BayesDel_noAF

Pathogenic

0.19

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.83

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.84

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.10

MetaSVM

Uncertain

0.75

MutationAssessor

Pathogenic

4.1

PhyloP100

7.8

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-3.4

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.87

MVP

0.82

MPC

0.45

ClinPred

0.080

GERP RS

4.0

PromoterAI

0.00060

Neutral

(source)

Varity_R

0.75

Mutation Taster

=93/7

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over