rs115841867

chr2-232527445-C-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.243C>T(p.His81=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00167 in 1,612,212 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (29 hom., cov: 32)
  • Exomes 𝑓: 0.00096 (24 hom.)
• Consequence: CHRND NM_000751.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.001951
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.635

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=-0.62).
• BP6: Variant 2-232527445-C-T is Benign according to our data. Variant chr2-232527445-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 128758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-232527445-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.635 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00844 (1282/151856) while in subpopulation AFR AF= 0.0297 (1232/41418). AF 95% confidence interval is 0.0284. There are 29 homozygotes in gnomad4. There are 631 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 29 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRND	NM_000751.3	c.243C>T	p.His81=	splice_region_variant, synonymous_variant	3/12	ENST00000258385.8
CHRND	NM_001311195.2	c.-29C>T		splice_region_variant, 5_prime_UTR_variant	3/10
CHRND	NM_001311196.2	c.-29C>T		splice_region_variant, 5_prime_UTR_variant	3/12
CHRND	NM_001256657.2	c.198+771C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRND	ENST00000258385.8	c.243C>T	p.His81=	splice_region_variant, synonymous_variant	3/12	1	NM_000751.3	P1

Frequencies

GnomAD3 genomes AF: 0.00840 AC: 1275 AN: 151734 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.0297

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00622

GnomAD3 exomes AF: 0.00210 AC: 527 AN: 251140 Hom.: 5 AF XY: 0.00139 AC XY: 189 AN XY: 135784

Gnomad AFR exome AF: 0.0298

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000969

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000963 AC: 1406 AN: 1460356 Hom.: 24 Cov.: 31 AF XY: 0.000838 AC XY: 609 AN XY: 726610

Gnomad4 AFR exome AF: 0.0315

Gnomad4 AMR exome AF: 0.000649

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000202

Gnomad4 OTH exome AF: 0.00156

GnomAD4 genome AF: 0.00844 AC: 1282 AN: 151856 Hom.: 29 Cov.: 32 AF XY: 0.00851 AC XY: 631 AN XY: 74164

Gnomad4 AFR AF: 0.0297

Gnomad4 AMR AF: 0.00223

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00147 Hom.: 5

Bravo AF: 0.00911

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 12, 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. -

Lethal multiple pterygium syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Mar 10, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
Cadd	Benign	9.4
Dann	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0020
dbscSNV1_RF	Benign	0.070
SpliceAI score (max)		0.12		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: rs115841867; hg19: chr2-233392155; COSMIC: COSV99286133; COSMIC: COSV99286133;