rs767503038

Positions:

• chr2-232543029-CCT-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_005199.5(CHRNG):​c.753_754del​(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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 6.12

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-232543029-CCT-C is Pathogenic according to our data. Variant chr2-232543029-CCT-C is described in ClinVar as [Pathogenic]. Clinvar id is 18342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-232543029-CCT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNG	NM_005199.5	c.753_754del	p.Val253AlafsTer44	frameshift_variant	7/12	ENST00000651502.1	NP_005190.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNG	ENST00000651502.1	c.753_754del	p.Val253AlafsTer44	frameshift_variant	7/12		NM_005199.5	ENSP00000498757	P1
CHRNG	ENST00000389492.3	c.597_598del	p.Val201AlafsTer44	frameshift_variant	6/11	1		ENSP00000374143

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152248 Hom.: 0 Cov.: 33

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

GnomAD3 exomes AF: 0.000163 AC: 41 AN: 251490 Hom.: 0 AF XY: 0.000140 AC XY: 19 AN XY: 135918

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 SAS exome AF: 0.000229

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.: 0 AF XY: 0.000216 AC XY: 157 AN XY: 727242

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.000301

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000212

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152366 Hom.: 0 Cov.: 33 AF XY: 0.000322 AC XY: 24 AN XY: 74502

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.000326

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000646 Hom.: 0

Bravo AF: 0.000314

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lethal multiple pterygium syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 21, 2023	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. -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 16, 2021	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Sep 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 18, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2024	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. -

Autosomal recessive multiple pterygium syndrome Pathogenic:3

Pathogenic, no assertion criteria provided	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Oct 28, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1. -

CHRNG-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Oct 26, 2018

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2016

- -

Autosomal recessive multiple pterygium syndrome;C1854678:Lethal multiple pterygium syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 20, 2022

- -

Abnormality of prenatal development or birth Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs767503038; hg19: chr2-233407739;