rs2289080

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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. 16/20 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

Publications

19 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: 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

CHRNG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 259667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNG	NM_005199.5 link	c.445G>A	p.Ala149Thr	missense_variant	Exon 5 of 12	ENST00000651502.1	NP_005190.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CHRNG	ENST00000651502.1 link	c.445G>A	p.Ala149Thr	missense_variant	Exon 5 of 12		NM_005199.5	ENSP00000498757.1
CHRNG	ENST00000485094.1 link	n.466G>A		non_coding_transcript_exon_variant	Exon 5 of 5	1
CHRNG	ENST00000389492.3 link	c.350+757G>A		intron_variant	Intron 4 of 10	1		ENSP00000374143.3

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

GnomAD2 exomes

AF:

0.0335

AC:

8415

AN:

251456

AF XY:

0.0312

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 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

African (AFR)

AF:

0.0272

AC:

910

AN:

33478

American (AMR)

AF:

0.0658

AC:

2943

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00708

AC:

185

AN:

26134

East Asian (EAS)

AF:

0.114

AC:

4526

AN:

39700

South Asian (SAS)

AF:

0.0290

AC:

2503

AN:

86258

European-Finnish (FIN)

AF:

0.0331

AC:

1769

AN:

53384

Middle Eastern (MID)

AF:

0.0217

AC:

125

AN:

5768

European-Non Finnish (NFE)

AF:

0.0182

AC:

20271

AN:

1111960

Other (OTH)

AF:

0.0291

AC:

1758

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

2208

4415

6623

8830

11038

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

842

1684

2526

3368

4210

<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:

0.0279

AC:

4244

AN:

152252

Hom.:

103

Cov.:

AF XY:

0.0285

AC XY:

2121

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.0286

AC:

1187

AN:

41542

American (AMR)

AF:

0.0439

AC:

671

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00519

AC:

AN:

3470

East Asian (EAS)

AF:

0.108

AC:

558

AN:

5176

South Asian (SAS)

AF:

0.0299

AC:

144

AN:

4818

European-Finnish (FIN)

AF:

0.0332

AC:

352

AN:

10608

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0182

AC:

1239

AN:

68016

Other (OTH)

AF:

0.0326

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

209

418

627

836

1045

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

150

200

250

<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:

0.0233

Hom.:

306

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

Nov 25, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Autosomal recessive multiple pterygium syndrome

Benign:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Congenital Myasthenic Syndrome, Dominant/Recessive

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Lethal multiple pterygium syndrome

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

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

PhyloP100

-0.018

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

Mutation Taster

=94/6

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over