rs2245601

Variant names:

• chr2-232526227-A-G
• rs2245601
• NM_000751.3:c.12A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-232526227-A-G
• chr2-232526227-A-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000751.3(CHRND):​c.12A>G​(p.Pro4Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.49 in 1,587,830 control chromosomes in the GnomAD database, including 189,261 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (16495 hom., cov: 31)
  • Exomes 𝑓: 0.49 (172766 hom.)
• Consequence: CHRND NM_000751.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -4.34
• Publications: 20 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-232526227-A-G is Benign according to our data. Variant chr2-232526227-A-G is described in ClinVar as [Benign]. Clinvar id is 128757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.34 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.668 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRND	NM_000751.3	c.12A>G	p.Pro4Pro	synonymous_variant	Exon 1 of 12	ENST00000258385.8	NP_000742.1
CHRND	NM_001256657.2	c.12A>G	p.Pro4Pro	synonymous_variant	Exon 1 of 11		NP_001243586.1
CHRND	NM_001311196.2	c.-260A>G		5_prime_UTR_variant	Exon 1 of 12		NP_001298125.1
CHRND	NM_001311195.2	c.-260A>G		5_prime_UTR_variant	Exon 1 of 10		NP_001298124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRND	ENST00000258385.8	c.12A>G	p.Pro4Pro	synonymous_variant	Exon 1 of 12	1	NM_000751.3	ENSP00000258385.3

Frequencies

GnomAD3 genomes AF: 0.465 AC: 69913 AN: 150440 Hom.: 16475 Cov.: 31

Gnomad AFR AF: 0.385

Gnomad AMI AF: 0.389

Gnomad AMR AF: 0.474

Gnomad ASJ AF: 0.486

Gnomad EAS AF: 0.688

Gnomad SAS AF: 0.517

Gnomad FIN AF: 0.518

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.484

Gnomad OTH AF: 0.437

GnomAD2 exomes AF: 0.504 AC: 125831 AN: 249842 AF XY: 0.502

Gnomad AFR exome AF: 0.378

Gnomad AMR exome AF: 0.551

Gnomad ASJ exome AF: 0.499

Gnomad EAS exome AF: 0.693

Gnomad FIN exome AF: 0.495

Gnomad NFE exome AF: 0.484

Gnomad OTH exome AF: 0.472

GnomAD4 exome AF: 0.492 AC: 707422 AN: 1437272 Hom.: 172766 Cov.: 50 AF XY: 0.493 AC XY: 352450 AN XY: 714824

African (AFR) AF: 0.383 AC: 12438 AN: 32450

American (AMR) AF: 0.554 AC: 24323 AN: 43910

Ashkenazi Jewish (ASJ) AF: 0.513 AC: 12943 AN: 25242

East Asian (EAS) AF: 0.656 AC: 25307 AN: 38568

South Asian (SAS) AF: 0.496 AC: 42634 AN: 85974

European-Finnish (FIN) AF: 0.518 AC: 26410 AN: 50936

Middle Eastern (MID) AF: 0.417 AC: 2293 AN: 5500

European-Non Finnish (NFE) AF: 0.485 AC: 532095 AN: 1095994

Other (OTH) AF: 0.494 AC: 28979 AN: 58698

GnomAD4 genome AF: 0.465 AC: 69978 AN: 150558 Hom.: 16495 Cov.: 31 AF XY: 0.468 AC XY: 34424 AN XY: 73528

African (AFR) AF: 0.385 AC: 15804 AN: 41088

American (AMR) AF: 0.475 AC: 7210 AN: 15192

Ashkenazi Jewish (ASJ) AF: 0.486 AC: 1679 AN: 3456

East Asian (EAS) AF: 0.687 AC: 3470 AN: 5048

South Asian (SAS) AF: 0.517 AC: 2400 AN: 4642

European-Finnish (FIN) AF: 0.518 AC: 5385 AN: 10386

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.484 AC: 32628 AN: 67452

Other (OTH) AF: 0.442 AC: 931 AN: 2108

Alfa AF: 0.472 Hom.: 22656

Bravo AF: 0.458

Asia WGS AF: 0.574 AC: 1992 AN: 3478

EpiCase AF: 0.479

EpiControl AF: 0.478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Jan 19, 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. -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 09, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lethal multiple pterygium syndrome Benign:2

Jan 13, 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 13, 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	-0.85
CADD	Benign	0.46
DANN	Benign	0.79
PhyloP100		-4.3
PromoterAI		-0.021	Neutral
Mutation Taster		=299/1	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: rs2245601; hg19: chr2-233390937; COSMIC: COSV51317778; COSMIC: COSV51317778;