2-232526593-C-G

Variant names:

Variant summary

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

The NM_000751.3(CHRND):c.117C>G(p.Asn39Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00349 in 1,613,824 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0034 ( 5 hom., cov: 33)

Exomes 𝑓: 0.0035 ( 54 hom. )

Consequence

CHRND
NM_000751.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 2.01

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 topological_domain Extracellular (size 223) in uniprot entity ACHD_HUMAN there are 10 pathogenic changes around while only 2 benign (83%) in NM_000751.3

BP4

Computational evidence support a benign effect (MetaRNN=0.009984076).

BP6

Variant 2-232526593-C-G is Benign according to our data. Variant chr2-232526593-C-G is described in ClinVar as [Benign]. Clinvar id is 195100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-232526593-C-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00345 (525/152312) while in subpopulation EAS AF= 0.0261 (135/5170). AF 95% confidence interval is 0.0225. There are 5 homozygotes in gnomad4. There are 280 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRND	NM_000751.3 link	c.117C>G	p.Asn39Lys	missense_variant	Exon 2 of 12	ENST00000258385.8	NP_000742.1	Q07001-1
CHRND	NM_001256657.2 link	c.117C>G	p.Asn39Lys	missense_variant	Exon 2 of 11		NP_001243586.1	Q07001-2
CHRND	NM_001311196.2 link	c.-155C>G		5_prime_UTR_variant	Exon 2 of 12		NP_001298125.1	Q07001
CHRND	NM_001311195.2 link	c.-155C>G		5_prime_UTR_variant	Exon 2 of 10		NP_001298124.1	Q07001B4E3W4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRND	ENST00000258385.8 link	c.117C>G	p.Asn39Lys	missense_variant	Exon 2 of 12	1	NM_000751.3	ENSP00000258385.3		Q07001-1

Frequencies

GnomAD3 genomes

AF:

0.00344

AC:

524

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000820

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0117

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0261

Gnomad SAS

AF:

0.00518

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00209

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00589

AC:

1480

AN:

251246

Hom.:

AF XY:

0.00531

AC XY:

722

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.000739

Gnomad AMR exome

AF:

0.0179

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.0260

Gnomad SAS exome

AF:

0.00320

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00218

Gnomad OTH exome

AF:

0.00359

GnomAD4 exome

AF:

0.00349

AC:

5103

AN:

1461512

Hom.:

Cov.:

AF XY:

0.00347

AC XY:

2524

AN XY:

727074

show subpopulations

Gnomad4 AFR exome

AF:

0.000448

Gnomad4 AMR exome

AF:

0.0167

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.0371

Gnomad4 SAS exome

AF:

0.00362

Gnomad4 FIN exome

AF:

0.000151

Gnomad4 NFE exome

AF:

0.00209

Gnomad4 OTH exome

AF:

0.00351

GnomAD4 genome

AF:

0.00345

AC:

525

AN:

152312

Hom.:

Cov.:

AF XY:

0.00376

AC XY:

280

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.000818

Gnomad4 AMR

AF:

0.0118

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0261

Gnomad4 SAS

AF:

0.00519

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00209

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00306

Hom.:

Bravo

AF:

0.00451

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.00535

AC:

649

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.00224

EpiControl

AF:

0.00225

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 31, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:3

Jun 04, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 01, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 29258548) -

Lethal multiple pterygium syndrome

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 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. -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital myasthenic syndrome

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.57

.;.;D

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.15

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.71

T;T;T

MetaRNN

Benign

0.010

T;T;T

MetaSVM

Benign

-0.38

MutationAssessor

Uncertain

2.2

.;M;M

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-4.0

D;D;D

REVEL

Uncertain

0.40

Sift

Benign

0.034

D;D;D

Sift4G

Uncertain

0.021

D;D;D

Polyphen

0.0050

.;.;B

Vest4

0.35, 0.35

MutPred

0.60

Gain of methylation at N39 (P = 0.0101);Gain of methylation at N39 (P = 0.0101);Gain of methylation at N39 (P = 0.0101);

MVP

0.89

MPC

0.32

ClinPred

0.043

GERP RS

3.8

Varity_R

0.35

gMVP

0.74

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