rs4790235

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000080.4(CHRNE):c.53G>T(p.Gly18Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0314 in 1,614,008 control chromosomes in the GnomAD database, including 2,014 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.032 ( 200 hom., cov: 32)

Exomes 𝑓: 0.031 ( 1814 hom. )

Consequence

CHRNE
NM_000080.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.570

Variant links:

Genes affected

CHRNE (HGNC:1966): (cholinergic receptor nicotinic epsilon subunit) Acetylcholine receptors at mature mammalian neuromuscular junctions are pentameric protein complexes composed of four subunits in the ratio of two alpha subunits to one beta, one epsilon, and one delta subunit. The acetylcholine receptor changes subunit composition shortly after birth when the epsilon subunit replaces the gamma subunit seen in embryonic receptors. Mutations in the epsilon subunit are associated with congenital myasthenic syndrome. [provided by RefSeq, Sep 2009]

CHRNE links:

C17orf107 (HGNC:37238): (chromosome 17 open reading frame 107)

C17orf107 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0014411211).

BP6

Variant 17-4902757-C-A is Benign according to our data. Variant chr17-4902757-C-A is described in ClinVar as [Benign]. Clinvar id is 128768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4902757-C-A is described in Lovd as [Benign]. Variant chr17-4902757-C-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNE	NM_000080.4 link	c.53G>T	p.Gly18Val	missense_variant	2/12	ENST00000649488.2	NP_000071.1	Q04844
C17orf107	NM_001145536.2 link	c.*2224C>A		3_prime_UTR_variant	3/3	ENST00000381365.4	NP_001139008.1	Q6ZR85

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CHRNE	ENST00000649488.2 link	c.53G>T	p.Gly18Val	missense_variant	2/12		NM_000080.4	ENSP00000497829.1	Q04844
C17orf107	ENST00000381365.4 link	c.*2224C>A		3_prime_UTR_variant	3/3	2	NM_001145536.2	ENSP00000370770.3	Q6ZR85
CHRNE	ENST00000649830.1 link	c.-881G>T		5_prime_UTR_premature_start_codon_gain_variant	2/11			ENSP00000496907.1	A0A3B3IRM1
CHRNE	ENST00000649830.1 link	c.-881G>T		5_prime_UTR_variant	2/11			ENSP00000496907.1	A0A3B3IRM1

Frequencies

GnomAD3 genomes

AF:

0.0319

AC:

4852

AN:

152026

Hom.:

200

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00824

Gnomad AMI

AF:

0.0749

Gnomad AMR

AF:

0.136

Gnomad ASJ

AF:

0.00548

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00746

Gnomad FIN

AF:

0.0376

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0269

Gnomad OTH

AF:

0.0430

GnomAD3 exomes

AF:

0.0487

AC:

12243

AN:

251414

Hom.:

1148

AF XY:

0.0412

AC XY:

5599

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.00714

Gnomad AMR exome

AF:

0.229

Gnomad ASJ exome

AF:

0.00516

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0108

Gnomad FIN exome

AF:

0.0348

Gnomad NFE exome

AF:

0.0249

Gnomad OTH exome

AF:

0.0391

GnomAD4 exome

AF:

0.0313

AC:

45770

AN:

1461864

Hom.:

1814

Cov.:

AF XY:

0.0298

AC XY:

21684

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00582

Gnomad4 AMR exome

AF:

0.219

Gnomad4 ASJ exome

AF:

0.00536

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0114

Gnomad4 FIN exome

AF:

0.0339

Gnomad4 NFE exome

AF:

0.0280

Gnomad4 OTH exome

AF:

0.0279

GnomAD4 genome

AF:

0.0319

AC:

4860

AN:

152144

Hom.:

200

Cov.:

AF XY:

0.0337

AC XY:

2510

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.00822

Gnomad4 AMR

AF:

0.136

Gnomad4 ASJ

AF:

0.00548

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00768

Gnomad4 FIN

AF:

0.0376

Gnomad4 NFE

AF:

0.0269

Gnomad4 OTH

AF:

0.0426

Alfa

AF:

0.0251

Hom.:

250

Bravo

AF:

0.0436

TwinsUK

AF:

0.0243

AC:

ALSPAC

AF:

0.0257

AC:

ESP6500AA

AF:

0.00817

AC:

ESP6500EA

AF:

0.0223

AC:

192

ExAC

AF:

0.0406

AC:

4935

Asia WGS

AF:

0.0100

AC:

AN:

3478

EpiCase

AF:

0.0233

EpiControl

AF:

0.0262

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 08, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 19, 2018	p.Gly18Val in exon 2 of CHRNE: This variant is classified as benign because it h as been identified in 23% (7902/34416) of Latino chromosomes, including 1073 hom ozygous individuals, by the Genome Aggregation Database (gnomAD, http://gnomad.b roadinstitute.org; dbSNP rs4790235). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Congenital myasthenic syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Congenital myasthenic syndrome 4A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.51

CADD

Benign

8.8

DANN

Benign

0.97

DEOGEN2

Benign

0.069

T;T

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.37

.;T

MetaRNN

Benign

0.0014

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

L;L

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.48

N;.

REVEL

Benign

0.13

Sift

Benign

0.56

T;.

Sift4G

Benign

0.55

T;.

Polyphen

0.084

B;B

Vest4

0.11

MPC

0.75

ClinPred

0.015

GERP RS

1.8

Varity_R

0.041

gMVP

0.34

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