rs767503038

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_005199.5(CHRNG):c.753_754delCT(p.Val253AlafsTer44) variant causes a frameshift change. The variant allele was found at a frequency of 0.000217 in 1,614,252 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

CHRNG
NM_005199.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:17

Conservation

PhyloP100: 6.12

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: 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: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 2-232543029-CCT-C is Pathogenic according to our data. Variant chr2-232543029-CCT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 18342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNG	NM_005199.5 link	c.753_754delCT	p.Val253AlafsTer44	frameshift_variant	Exon 7 of 12	ENST00000651502.1	NP_005190.4	P07510-1A0A6F7YAP6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNG	ENST00000651502.1 link	c.753_754delCT	p.Val253AlafsTer44	frameshift_variant	Exon 7 of 12		NM_005199.5	ENSP00000498757.1		P07510-1
CHRNG	ENST00000389492.3 link	c.597_598delCT	p.Val201AlafsTer44	frameshift_variant	Exon 6 of 11	1		ENSP00000374143.3		P07510-2

Frequencies

GnomAD3 genomes

AF:

0.000250

AC:

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000163

AC:

AN:

251490

AF XY:

0.000140

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000217

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000213

AC:

311

AN:

1461886

Hom.:

AF XY:

0.000216

AC XY:

157

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33480

American (AMR)

AF:

0.000224

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26136

East Asian (EAS)

AF:

0.000176

AC:

AN:

39700

South Asian (SAS)

AF:

0.000301

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000212

AC:

236

AN:

1112008

Other (OTH)

AF:

0.000315

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000256

AC:

AN:

152366

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.000385

AC:

AN:

41584

American (AMR)

AF:

0.000326

AC:

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5194

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000235

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.0000646

Hom.:

Bravo

AF:

0.000314

EpiCase

AF:

0.000164

EpiControl

AF:

0.000296

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Lethal multiple pterygium syndrome

Pathogenic:5

Apr 01, 2015

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Feb 21, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CHRNG c.753_754delCT (p.Val253AlafsX44) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00016 in 251490 control chromosomes. c.753_754delCT has been reported in the literature in multiple individuals affected with lethal and Escobar variant multiple pterygium syndrome. These data indicate that the variant is very likely to be associated with disease. 11 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The frameshift c.753_754del(p.Val253AlafsTer44) variant in CHRNG gene has been reported previously in homozygous and compound heterozygous states in individual(s) affected with Multiple pterygium syndrome (Chong JX, et. al., 2015; Kariminejad A, et. al., 2016). The p.Val253AlafsTer44 variant has been reported with allele frequency of 0.02% in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). This variant causes a frameshift starting with codon Valine 253, changes this amino acid to Alanine residue, and creates a premature Stop codon at position 44 of the new reading frame, denoted p.Val253AlafsTer44. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -

May 22, 2022

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.017%). Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000018342). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

May 01, 2025

Department of Reproductive Genetics, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The variant in the CHRNG gene results in a frameshift and introduces a premature termination codon at position 44 downstream of codon 253 (p.Val253AlafsTer44). This was predicted to cause nonsense-mediated mRNA decay (NMD), leading to loss of protein expression. Loss-of-function was a well-established mechanism of disease for CHRNG-related disorders.This variant has been observed in multiple affected individuals reported in the literature and submitted to ClinVar (Variation ID: 18342) as Pathogenic. -

not provided

Pathogenic:4

Jul 18, 2023

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Val253Alafs*44) in the CHRNG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHRNG are known to be pathogenic (PMID: 16826520). This variant is present in population databases (rs767503038, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with lethal and Escobar variant multiple pterygium syndrome (PMID: 16826531, 22167768, 24038971, 25608830, 27245440). ClinVar contains an entry for this variant (Variation ID: 18342). For these reasons, this variant has been classified as Pathogenic. -

Apr 16, 2021

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25957469, 25608830, 30868735, 24038971, 22167768, 34426522, 31589614, 33250842, 32587836, 16826531) -

Sep 15, 2021

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive multiple pterygium syndrome

Pathogenic:3

Apr 01, 2015

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Oct 28, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1. -

Autosomal recessive multiple pterygium syndrome;C1854678:Lethal multiple pterygium syndrome

Pathogenic:2

Apr 22, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2_Supporting+PVS1+PM3_VeryStrong+PP1 -

CHRNG-related disorder

Pathogenic:1

Oct 26, 2018

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CHRNG c.753_754delCT (p.Val253AlafsTer44) variant results in a frameshift, and is predicted to result in premature termination of the protein. This variant has been reported in six studies and is found in a total of seven probands including four in a homozygous state and three in a compound heterozygous state (Morgan et al. 2006; Vogt et al. 2012; Robinson et al. 2013; Chong et al. 2015; Kariminejad et al. 2016; Bayram et al. 2016). The variant has been described in probands with both lethal multiple pterygium syndrome and non-lethal (Escobar) phenotypes. Control data are unavailable for this variant, but it is reported at a frequency of 0.00038 in the African population of the Exome Aggregation Consortium. Based on the evidence, the p.Val253AlafsTer44 variant is classified as pathogenic for CHRNG-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Inborn genetic diseases

Pathogenic:1

Dec 06, 2016

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Abnormality of prenatal development or birth

Pathogenic:1

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

6.1

Mutation Taster

=4/196

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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