rs2278478

Positions:

• chr2-232526753-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000751.3(CHRND):​c.198+79A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.277 in 1,510,956 control chromosomes in the GnomAD database, including 60,884 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.24 (4979 hom., cov: 32)
  • Exomes 𝑓: 0.28 (55905 hom.)
• Consequence: CHRND NM_000751.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.89

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 2-232526753-A-G is Benign according to our data. Variant chr2-232526753-A-G is described in ClinVar as [Benign]. Clinvar id is 680135.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.345 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRND	NM_000751.3	c.198+79A>G		intron_variant		ENST00000258385.8
CHRND	NM_001256657.2	c.198+79A>G		intron_variant
CHRND	NM_001311195.2	c.-74+79A>G		intron_variant
CHRND	NM_001311196.2	c.-74+79A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRND	ENST00000258385.8	c.198+79A>G		intron_variant		1	NM_000751.3	P1

Frequencies

GnomAD3 genomes AF: 0.237 AC: 36013 AN: 152000 Hom.: 4956 Cov.: 32

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.337

Gnomad ASJ AF: 0.303

Gnomad EAS AF: 0.359

Gnomad SAS AF: 0.358

Gnomad FIN AF: 0.238

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.273

Gnomad OTH AF: 0.251

GnomAD4 exome AF: 0.282 AC: 383116 AN: 1358838 Hom.: 55905 AF XY: 0.284 AC XY: 192967 AN XY: 678310

Gnomad4 AFR exome AF: 0.0934

Gnomad4 AMR exome AF: 0.443

Gnomad4 ASJ exome AF: 0.312

Gnomad4 EAS exome AF: 0.364

Gnomad4 SAS exome AF: 0.354

Gnomad4 FIN exome AF: 0.241

Gnomad4 NFE exome AF: 0.274

Gnomad4 OTH exome AF: 0.277

GnomAD4 genome AF: 0.237 AC: 36057 AN: 152118 Hom.: 4979 Cov.: 32 AF XY: 0.240 AC XY: 17851 AN XY: 74362

Gnomad4 AFR AF: 0.103

Gnomad4 AMR AF: 0.338

Gnomad4 ASJ AF: 0.303

Gnomad4 EAS AF: 0.359

Gnomad4 SAS AF: 0.359

Gnomad4 FIN AF: 0.238

Gnomad4 NFE AF: 0.273

Gnomad4 OTH AF: 0.259

Alfa AF: 0.247 Hom.: 632

Bravo AF: 0.242

Asia WGS AF: 0.395 AC: 1370 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.3
DANN	Benign	0.46

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: rs2278478; hg19: chr2-233391463; COSMIC: COSV51317711; COSMIC: COSV51317711;