rs142063328

Variant names:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM5BP6BS1BS2

The NM_000751.3(CHRND):c.919C>T(p.Pro307Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00148 in 1,613,976 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P307L) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00083 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0015 ( 2 hom. )

Consequence

CHRND
NM_000751.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:2

Conservation

PhyloP100: 6.09

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 -7 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-232531451-C-T is described in Lovd as [Pathogenic].

BP6

Variant 2-232531450-C-T is Benign according to our data. Variant chr2-232531450-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 281423.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=7}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000834 (127/152234) while in subpopulation NFE AF= 0.00134 (91/68000). AF 95% confidence interval is 0.00112. There are 1 homozygotes in gnomad4. There are 61 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRND	NM_000751.3 link	c.919C>T	p.Pro307Ser	missense_variant	Exon 8 of 12	ENST00000258385.8	NP_000742.1	Q07001-1
CHRND	NM_001256657.2 link	c.874C>T	p.Pro292Ser	missense_variant	Exon 7 of 11		NP_001243586.1	Q07001-2
CHRND	NM_001311196.2 link	c.616C>T	p.Pro206Ser	missense_variant	Exon 8 of 12		NP_001298125.1	Q07001
CHRND	NM_001311195.2 link	c.337C>T	p.Pro113Ser	missense_variant	Exon 6 of 10		NP_001298124.1	Q07001B4E3W4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRND	ENST00000258385.8 link	c.919C>T	p.Pro307Ser	missense_variant	Exon 8 of 12	1	NM_000751.3	ENSP00000258385.3		Q07001-1

Frequencies

GnomAD3 genomes

AF:

0.000835

AC:

127

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00131

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:

0.00134

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00103

AC:

259

AN:

251440

Hom.:

AF XY:

0.000876

AC XY:

119

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.00208

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00149

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00155

AC:

2262

AN:

1461742

Hom.:

Cov.:

AF XY:

0.00142

AC XY:

1035

AN XY:

727180

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.00233

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00187

Gnomad4 OTH exome

AF:

0.00118

GnomAD4 genome

AF:

0.000834

AC:

127

AN:

152234

Hom.:

Cov.:

AF XY:

0.000819

AC XY:

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.00131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00134

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00129

Hom.:

Bravo

AF:

0.00116

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.000865

AC:

105

EpiCase

AF:

0.000927

EpiControl

AF:

0.00207

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:6Benign:1

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 17, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1, PP3 -

Oct 26, 2023

Revvity Omics, Revvity

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 23, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 12, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27104957) -

Lethal multiple pterygium syndrome

Uncertain:1Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital myasthenic syndrome

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Lethal multiple pterygium syndrome;C4225370:Congenital myasthenic syndrome 3C;C4225371:Congenital myasthenic syndrome 3B;C4225372:Congenital myasthenic syndrome 3A

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.53

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.78

.;D

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.95

D;D

M_CAP

Pathogenic

0.33

MetaRNN

Uncertain

0.71

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.0

.;H

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-7.8

D;D

REVEL

Pathogenic

0.87

Sift

Uncertain

0.010

D;D

Sift4G

Uncertain

0.0050

D;D

Polyphen

1.0

.;D

Vest4

0.90

MVP

1.0

MPC

0.88

ClinPred

0.79

GERP RS

6.1

Varity_R

0.84

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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