NM_000751.3:c.1047+9T>C

Variant names:

• chr2-232531665-T-C
• rs3762528
• NM_000751.3:c.1047+9T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 13 publications found

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]

CHRND Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 3A

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• congenital myasthenic syndrome 3B

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Genomics England PanelApp
• congenital myasthenic syndrome 3C

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 128755.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
CHRND	NM_000751.3	c.1047+9T>C		intron_variant	Intron 9 of 11	ENST00000258385.8	NP_000742.1
CHRND	NM_001256657.2	c.1002+9T>C		intron_variant	Intron 8 of 10		NP_001243586.1
CHRND	NM_001311196.2	c.744+9T>C		intron_variant	Intron 9 of 11		NP_001298125.1
CHRND	NM_001311195.2	c.465+9T>C		intron_variant	Intron 7 of 9		NP_001298124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRND	ENST00000258385.8	c.1047+9T>C		intron_variant	Intron 9 of 11	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

GnomAD2 exomes AF: 0.0693 AC: 17281 AN: 249274 AF XY: 0.0668

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 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

African (AFR) AF: 0.0862 AC: 2880 AN: 33402

American (AMR) AF: 0.0978 AC: 4375 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0495 AC: 1293 AN: 26116

East Asian (EAS) AF: 0.0705 AC: 2798 AN: 39686

South Asian (SAS) AF: 0.0588 AC: 5072 AN: 86190

European-Finnish (FIN) AF: 0.0606 AC: 3095 AN: 51112

Middle Eastern (MID) AF: 0.0636 AC: 366 AN: 5752

European-Non Finnish (NFE) AF: 0.0666 AC: 73880 AN: 1108860

Other (OTH) AF: 0.0672 AC: 4047 AN: 60264

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

African (AFR) AF: 0.0838 AC: 3479 AN: 41496

American (AMR) AF: 0.100 AC: 1535 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0501 AC: 174 AN: 3472

East Asian (EAS) AF: 0.0751 AC: 388 AN: 5164

South Asian (SAS) AF: 0.0545 AC: 263 AN: 4822

European-Finnish (FIN) AF: 0.0581 AC: 616 AN: 10594

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0639 AC: 4343 AN: 67980

Other (OTH) AF: 0.0631 AC: 133 AN: 2108

Alfa AF: 0.0666 Hom.: 381

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

Sep 23, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Lethal multiple pterygium syndrome Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Congenital myasthenic syndrome Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-0.34
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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