2-232530046-C-T

Position:

• chr2-232530046-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1 BS1 BS2

The NM_000751.3(CHRND):​c.727C>T​(p.Arg243Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000292 in 1,614,166 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00041 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (3 hom.)
• Consequence: CHRND NM_000751.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:3
• Conservation: PhyloP100: 1.80

Genes affected

CHRND (HGNC:1965): (cholinergic receptor nicotinic delta subunit) The acetylcholine receptor of muscle has 5 subunits of 4 different types: 2 alpha and 1 each of beta, gamma and delta subunits. After acetylcholine binding, the receptor undergoes an extensive conformation change that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. Defects in this gene are a cause of multiple pterygium syndrome lethal type (MUPSL), congenital myasthenic syndrome slow-channel type (SCCMS), and congenital myasthenic syndrome fast-channel type (FCCMS). Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2015]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PM1: In a topological_domain Extracellular (size 223) in uniprot entity ACHD_HUMAN there are 10 pathogenic changes around while only 2 benign (83%) in NM_000751.3
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00028 (409/1461872) while in subpopulation MID AF= 0.0153 (88/5768). AF 95% confidence interval is 0.0127. There are 3 homozygotes in gnomad4_exome. There are 208 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRND	NM_000751.3	c.727C>T	p.Arg243Cys	missense_variant	7/12	ENST00000258385.8	NP_000742.1
CHRND	NM_001256657.2	c.682C>T	p.Arg228Cys	missense_variant	6/11		NP_001243586.1
CHRND	NM_001311196.2	c.424C>T	p.Arg142Cys	missense_variant	7/12		NP_001298125.1
CHRND	NM_001311195.2	c.239-1306C>T		intron_variant			NP_001298124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRND	ENST00000258385.8	c.727C>T	p.Arg243Cys	missense_variant	7/12	1	NM_000751.3	ENSP00000258385.3

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152176 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000295 AC: 74 AN: 251254 Hom.: 0 AF XY: 0.000280 AC XY: 38 AN XY: 135834

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000282

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000280 AC: 409 AN: 1461872 Hom.: 3 Cov.: 32 AF XY: 0.000286 AC XY: 208 AN XY: 727234

Gnomad4 AFR exome AF: 0.000986

Gnomad4 AMR exome AF: 0.000626

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000196

Gnomad4 OTH exome AF: 0.000530

GnomAD4 genome AF: 0.000414 AC: 63 AN: 152294 Hom.: 1 Cov.: 32 AF XY: 0.000389 AC XY: 29 AN XY: 74468

Gnomad4 AFR AF: 0.000626

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000293 Hom.: 0

Bravo AF: 0.000525

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000255 AC: 31

EpiCase AF: 0.000164

EpiControl AF: 0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 23, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 32528171) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 19, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 05, 2023	- -

Lethal multiple pterygium syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 243 of the CHRND protein (p.Arg243Cys). This variant is present in population databases (rs201733876, gnomAD 0.06%). This missense change has been observed in individual(s) with clinical features of CHRND-related conditions (PMID: 32528171). ClinVar contains an entry for this variant (Variation ID: 283138). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CHRND protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

Congenital myasthenic syndrome 3A Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

May 04, 2022

The heterozygous p.Arg243Cys variant in CHRND was identified by our study in 1 individual with congenital myasthenic syndrome 3A. The variant has not been previously reported in individuals with congenital myasthenic syndrome 3A but has been identified in 0.06% (14/24950) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs201733876). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 283138) as having uncertain significance by multiple submitters. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg243Cys variant is uncertain. ACMG/AMP Criteria applied: none (Richards 2015). -

Congenital myasthenic syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Lethal multiple pterygium syndrome;C4225370:Congenital myasthenic syndrome 3C;C4225371:Congenital myasthenic syndrome 3B;C4225372:Congenital myasthenic syndrome 3A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Aug 17, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.84	.;D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.57	D;D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Pathogenic	3.5	.;H
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-4.9	D;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	.;D
Vest4		0.61
MVP		1.0
MPC		1.0
ClinPred		0.14	T
GERP RS		5.2
Varity_R		0.48
gMVP		0.74

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: rs201733876; hg19: chr2-233394756; COSMIC: COSV51320564; COSMIC: COSV51320564;