rs41265127

Positions:

chr2-232531393-C-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_000751.3(CHRND):c.862C>G(p.Gln288Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0031 in 1,613,830 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0023 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0032 ( 11 hom. )

Consequence

CHRND
NM_000751.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 7.87

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a transmembrane_region Helical (size 21) in uniprot entity ACHD_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_000751.3

BP4

Computational evidence support a benign effect (MetaRNN=0.057361603).

BP6

Variant 2-232531393-C-G is Benign according to our data. Variant chr2-232531393-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 198749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-232531393-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00231 (352/152110) while in subpopulation NFE AF= 0.00312 (212/67970). AF 95% confidence interval is 0.00277. There are 0 homozygotes in gnomad4. There are 158 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 11 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CHRND	NM_000751.3 linkuse as main transcript	c.862C>G	p.Gln288Glu	missense_variant	8/12	ENST00000258385.8	NP_000742.1
CHRND	NM_001256657.2 linkuse as main transcript	c.817C>G	p.Gln273Glu	missense_variant	7/11		NP_001243586.1
CHRND	NM_001311196.2 linkuse as main transcript	c.559C>G	p.Gln187Glu	missense_variant	8/12		NP_001298125.1
CHRND	NM_001311195.2 linkuse as main transcript	c.280C>G	p.Gln94Glu	missense_variant	6/10		NP_001298124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRND	ENST00000258385.8 linkuse as main transcript	c.862C>G	p.Gln288Glu	missense_variant	8/12	1	NM_000751.3	ENSP00000258385	P1	Q07001-1

Frequencies

GnomAD3 genomes

AF:

0.00232

AC:

352

AN:

151992

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000942

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

Gnomad ASJ

AF:

0.0112

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000209

Gnomad FIN

AF:

0.00273

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00312

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.00265

AC:

667

AN:

251240

Hom.:

AF XY:

0.00253

AC XY:

343

AN XY:

135806

show subpopulations

Gnomad AFR exome

AF:

0.000739

Gnomad AMR exome

AF:

0.00211

Gnomad ASJ exome

AF:

0.0129

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00231

Gnomad NFE exome

AF:

0.00333

Gnomad OTH exome

AF:

0.00391

GnomAD4 exome

AF:

0.00318

AC:

4646

AN:

1461720

Hom.:

Cov.:

AF XY:

0.00313

AC XY:

2274

AN XY:

727150

show subpopulations

Gnomad4 AFR exome

AF:

0.000597

Gnomad4 AMR exome

AF:

0.00208

Gnomad4 ASJ exome

AF:

0.0118

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00246

Gnomad4 NFE exome

AF:

0.00350

Gnomad4 OTH exome

AF:

0.00323

GnomAD4 genome

AF:

0.00231

AC:

352

AN:

152110

Hom.:

Cov.:

AF XY:

0.00212

AC XY:

158

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.000940

Gnomad4 AMR

AF:

0.00183

Gnomad4 ASJ

AF:

0.0112

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000209

Gnomad4 FIN

AF:

0.00273

Gnomad4 NFE

AF:

0.00312

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00403

Hom.:

Bravo

AF:

0.00236

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00547

AC:

ExAC

AF:

0.00251

AC:

305

EpiCase

AF:

0.00213

EpiControl

AF:

0.00308

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	CHRND: BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 25, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 20, 2015	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 17, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Lethal multiple pterygium syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -

Congenital myasthenic syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.44

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

.;D

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Benign

0.046

MetaRNN

Benign

0.057

T;T

MetaSVM

Uncertain

0.50

MutationAssessor

Pathogenic

3.1

.;M

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-2.5

N;N

REVEL

Pathogenic

0.85

Sift

Uncertain

0.0070

D;D

Sift4G

Uncertain

0.021

D;D

Polyphen

1.0

.;D

Vest4

0.89

MVP

0.99

MPC

0.92

ClinPred

0.057

GERP RS

5.9

Varity_R

0.86

gMVP

0.78

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over