rs3762528

Positions:

• chr2-232531665-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000751.3(CHRND):​c.1047+9T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0677 in 1,608,224 control chromosomes in the GnomAD database, including 3,848 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.073 (430 hom., cov: 30)
  • Exomes 𝑓: 0.067 (3418 hom.)
• Consequence: CHRND NM_000751.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.341

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-232531665-T-C is Benign according to our data. Variant chr2-232531665-T-C is described in ClinVar as [Benign]. Clinvar id is 128755.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-232531665-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0962 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRND	NM_000751.3	c.1047+9T>C		intron_variant		ENST00000258385.8	NP_000742.1
CHRND	NM_001256657.2	c.1002+9T>C		intron_variant			NP_001243586.1
CHRND	NM_001311196.2	c.744+9T>C		intron_variant			NP_001298125.1
CHRND	NM_001311195.2	c.465+9T>C		intron_variant			NP_001298124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRND	ENST00000258385.8	c.1047+9T>C		intron_variant		1	NM_000751.3	ENSP00000258385.3

Frequencies

GnomAD3 genomes AF: 0.0726 AC: 11037 AN: 152012 Hom.: 429 Cov.: 30

Gnomad AFR AF: 0.0837

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.0501

Gnomad EAS AF: 0.0753

Gnomad SAS AF: 0.0549

Gnomad FIN AF: 0.0581

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0639

Gnomad OTH AF: 0.0642

GnomAD3 exomes AF: 0.0693 AC: 17281 AN: 249274 Hom.: 676 AF XY: 0.0668 AC XY: 9012 AN XY: 134996

Gnomad AFR exome AF: 0.0856

Gnomad AMR exome AF: 0.0991

Gnomad ASJ exome AF: 0.0472

Gnomad EAS exome AF: 0.0748

Gnomad SAS exome AF: 0.0595

Gnomad FIN exome AF: 0.0600

Gnomad NFE exome AF: 0.0633

Gnomad OTH exome AF: 0.0684

GnomAD4 exome AF: 0.0672 AC: 97806 AN: 1456094 Hom.: 3418 Cov.: 31 AF XY: 0.0663 AC XY: 48075 AN XY: 724758

Gnomad4 AFR exome AF: 0.0862

Gnomad4 AMR exome AF: 0.0978

Gnomad4 ASJ exome AF: 0.0495

Gnomad4 EAS exome AF: 0.0705

Gnomad4 SAS exome AF: 0.0588

Gnomad4 FIN exome AF: 0.0606

Gnomad4 NFE exome AF: 0.0666

Gnomad4 OTH exome AF: 0.0672

GnomAD4 genome AF: 0.0726 AC: 11045 AN: 152130 Hom.: 430 Cov.: 30 AF XY: 0.0727 AC XY: 5410 AN XY: 74382

Gnomad4 AFR AF: 0.0838

Gnomad4 AMR AF: 0.100

Gnomad4 ASJ AF: 0.0501

Gnomad4 EAS AF: 0.0751

Gnomad4 SAS AF: 0.0545

Gnomad4 FIN AF: 0.0581

Gnomad4 NFE AF: 0.0639

Gnomad4 OTH AF: 0.0631

Alfa AF: 0.0633 Hom.: 163

Bravo AF: 0.0757

Asia WGS AF: 0.0700 AC: 246 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Lethal multiple pterygium syndrome Benign:2

Benign, 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 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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Congenital myasthenic syndrome Benign:1

Benign, 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 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
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.8
DANN	Benign	0.58

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: rs3762528; hg19: chr2-233396375; COSMIC: COSV51331483; COSMIC: COSV51331483;