rs55921262

chr2-232526596-G-Achr2-232526596-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000751.3(CHRND):c.120G>A(p.Lys40=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0346 in 1,613,792 control chromosomes in the GnomAD database, including 1,284 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (129 hom., cov: 33)
  • Exomes 𝑓: 0.035 (1155 hom.)
• Consequence: CHRND NM_000751.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.75

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=-0.54).
• BP6: Variant 2-232526596-G-A is Benign according to our data. Variant chr2-232526596-G-A is described in ClinVar as [Benign]. Clinvar id is 128756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-232526596-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.75 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0311 (4735/152296) while in subpopulation NFE AF= 0.0409 (2781/68020). AF 95% confidence interval is 0.0396. There are 129 homozygotes in gnomad4. There are 2446 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 129 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRND	NM_000751.3	c.120G>A	p.Lys40=	synonymous_variant	2/12	ENST00000258385.8
CHRND	NM_001256657.2	c.120G>A	p.Lys40=	synonymous_variant	2/11
CHRND	NM_001311195.2	c.-152G>A		5_prime_UTR_variant	2/10
CHRND	NM_001311196.2	c.-152G>A		5_prime_UTR_variant	2/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRND	ENST00000258385.8	c.120G>A	p.Lys40=	synonymous_variant	2/12	1	NM_000751.3	P1

Frequencies

GnomAD3 genomes AF: 0.0311 AC: 4737 AN: 152178 Hom.: 129 Cov.: 33

Gnomad AFR AF: 0.00620

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0303

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.0978

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0409

Gnomad OTH AF: 0.0354

GnomAD3 exomes AF: 0.0314 AC: 7882 AN: 251246 Hom.: 216 AF XY: 0.0312 AC XY: 4243 AN XY: 135884

Gnomad AFR exome AF: 0.00659

Gnomad AMR exome AF: 0.0195

Gnomad ASJ exome AF: 0.0147

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00519

Gnomad FIN exome AF: 0.0945

Gnomad NFE exome AF: 0.0400

Gnomad OTH exome AF: 0.0341

GnomAD4 exome AF: 0.0350 AC: 51170 AN: 1461496 Hom.: 1155 Cov.: 34 AF XY: 0.0344 AC XY: 24979 AN XY: 727064

Gnomad4 AFR exome AF: 0.00541

Gnomad4 AMR exome AF: 0.0203

Gnomad4 ASJ exome AF: 0.0145

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00482

Gnomad4 FIN exome AF: 0.0874

Gnomad4 NFE exome AF: 0.0385

Gnomad4 OTH exome AF: 0.0285

GnomAD4 genome AF: 0.0311 AC: 4735 AN: 152296 Hom.: 129 Cov.: 33 AF XY: 0.0329 AC XY: 2446 AN XY: 74458

Gnomad4 AFR AF: 0.00618

Gnomad4 AMR AF: 0.0303

Gnomad4 ASJ AF: 0.0150

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00559

Gnomad4 FIN AF: 0.0978

Gnomad4 NFE AF: 0.0409

Gnomad4 OTH AF: 0.0350

Alfa AF: 0.0339 Hom.: 44

Bravo AF: 0.0246

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0385

EpiControl AF: 0.0411

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 26, 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. -
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. -

Lethal multiple pterygium syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 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	-0.54
Cadd	Benign	11
Dann	Benign	0.70

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: rs55921262; hg19: chr2-233391306;