rs148468628

chr2-232540061-G-Achr2-232540061-G-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

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). Synonymous variant affecting the same amino acid position (i.e. R42R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0025 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0029 (7 hom.)
• Consequence: CHRNG NM_005199.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 7.76

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 Benign. Variant got -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 id is 376837.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=1}. Variant chr2-232540061-G-A is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNG	NM_005199.5	c.125G>A	p.Arg42Gln	missense_variant	2/12	ENST00000651502.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNG	ENST00000651502.1	c.125G>A	p.Arg42Gln	missense_variant	2/12		NM_005199.5	P1
CHRNG	ENST00000389492.3	c.125G>A	p.Arg42Gln	missense_variant	2/11	1
CHRNG	ENST00000485094.1	n.146G>A		non_coding_transcript_exon_variant	2/5	1

Frequencies

GnomAD3 genomes AF: 0.00254 AC: 386 AN: 152226 Hom.: 4 Cov.: 33

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

GnomAD3 exomes AF: 0.00229 AC: 576 AN: 251312 Hom.: 1 AF XY: 0.00209 AC XY: 284 AN XY: 135838

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 SAS exome AF: 0.0000327

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.: 7 Cov.: 33 AF XY: 0.00278 AC XY: 2023 AN XY: 727240

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.00203

Gnomad4 ASJ exome AF: 0.00528

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000468

Gnomad4 NFE exome AF: 0.00340

Gnomad4 OTH exome AF: 0.00320

GnomAD4 genome AF: 0.00252 AC: 384 AN: 152344 Hom.: 4 Cov.: 33 AF XY: 0.00251 AC XY: 187 AN XY: 74492

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.00261

Gnomad4 ASJ AF: 0.00691

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000847

Gnomad4 NFE AF: 0.00422

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00332 Hom.: 3

Bravo AF: 0.00240

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00326 AC: 28

ExAC AF: 0.00247 AC: 300

EpiCase AF: 0.00354

EpiControl AF: 0.00391

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:6

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 04, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 27, 2020	This variant is associated with the following publications: (PMID: 30467950) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	CHRNG: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2022	Variant summary: CHRNG c.125G>A (p.Arg42Gln) results in a conservative amino acid change located in the Neurotransmitter-gated ion-channel ligand-binding domain (IPR006202) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0023 in 282714 control chromosomes, predominantly at a frequency of 0.0038 within the Non-Finnish European subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in CHRNG causing Lethal Multiple Pterygium Syndrome - CHRNG Related phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Six ClinVar submitters have assessed the variant since 2014: two have classified the variant as of uncertain significance and four as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The CHRNG p.Arg42Gln variant was not identified in the literature but was identified in dbSNP (ID: rs148468628) and ClinVar (classified as likely benign by Invitae and Center for Pediatric Genomic Medicine, Children's Mercy Hospital, and as uncertain significance by CeGat Praxis fuer Humangenetik Tuebingen). The variant was identified in control databases in 661 of 282714 chromosomes (3 homozygous) at a frequency of 0.002338 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 52 of 10364 chromosomes (freq: 0.005017), European (non-Finnish) in 493 of 129072 chromosomes (freq: 0.00382), Other in 18 of 7222 chromosomes (freq: 0.002492), Latino in 67 of 35412 chromosomes (freq: 0.001892), European (Finnish) in 18 of 25114 chromosomes (freq: 0.000717), African in 11 of 24962 chromosomes (freq: 0.000441), East Asian in 1 of 19952 chromosomes (freq: 0.00005), and South Asian in 1 of 30616 chromosomes (freq: 0.000033). The p.Arg42 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Autosomal recessive multiple pterygium syndrome Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

CHRNG-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 07, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Lethal multiple pterygium syndrome Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Pathogenic	0.19
Cadd	Uncertain	24
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	D;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.84	T;T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.10	T;T
MetaSVM	Uncertain	0.75	D
MutationAssessor	Pathogenic	4.1	H;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;.
Vest4		0.87
MVP		0.82
MPC		0.45
ClinPred		0.080	T
GERP RS		4.0
Varity_R		0.75

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

Other links and lift over

dbSNP: rs148468628; hg19: chr2-233404771; COSMIC: COSV51330914; COSMIC: COSV51330914;