rs2245601

chr2-232526227-A-Gchr2-232526227-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000751.3(CHRND):c.12A>G(p.Pro4=) 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:7
• Conservation: PhyloP100: -4.34

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 -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. Variant chr2-232526227-A-G is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
CHRND	NM_000751.3	c.12A>G	p.Pro4=	synonymous_variant	1/12	ENST00000258385.8
CHRND	NM_001256657.2	c.12A>G	p.Pro4=	synonymous_variant	1/11
CHRND	NM_001311195.2	c.-260A>G		5_prime_UTR_variant	1/10
CHRND	NM_001311196.2	c.-260A>G		5_prime_UTR_variant	1/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRND	ENST00000258385.8	c.12A>G	p.Pro4=	synonymous_variant	1/12	1	NM_000751.3	P1

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

GnomAD3 exomes AF: 0.504 AC: 125831 AN: 249842 Hom.: 32418 AF XY: 0.502 AC XY: 67874 AN XY: 135186

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 SAS exome AF: 0.490

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

Gnomad4 AFR exome AF: 0.383

Gnomad4 AMR exome AF: 0.554

Gnomad4 ASJ exome AF: 0.513

Gnomad4 EAS exome AF: 0.656

Gnomad4 SAS exome AF: 0.496

Gnomad4 FIN exome AF: 0.518

Gnomad4 NFE exome AF: 0.485

Gnomad4 OTH exome AF: 0.494

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

Gnomad4 AFR AF: 0.385

Gnomad4 AMR AF: 0.475

Gnomad4 ASJ AF: 0.486

Gnomad4 EAS AF: 0.687

Gnomad4 SAS AF: 0.517

Gnomad4 FIN AF: 0.518

Gnomad4 NFE AF: 0.484

Gnomad4 OTH AF: 0.442

Alfa AF: 0.472 Hom.: 19484

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:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 19, 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 09, 2015	- -

Lethal multiple pterygium syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Congenital myasthenic syndrome Benign:1

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 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

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: rs2245601; hg19: chr2-233390937; COSMIC: COSV51317778; COSMIC: COSV51317778;