rs4790235

Variant names:

• chr17-4902757-C-A
• rs4790235
• NM_000080.4:c.53G>T

Your query was ambiguous. Multiple possible variants found:

• chr17-4902757-C-A
• chr17-4902757-C-G
• chr17-4902757-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G18S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.032 (200 hom., cov: 32)
  • Exomes 𝑓: 0.031 (1814 hom.)
• Consequence: CHRNE NM_000080.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.570
• Publications: 17 publications found

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]

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 128768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
CHRNE	NM_000080.4	c.53G>T	p.Gly18Val	missense_variant	Exon 2 of 12	ENST00000649488.2	NP_000071.1
C17orf107	NM_001145536.2	c.*2224C>A		3_prime_UTR_variant	Exon 3 of 3	ENST00000381365.4	NP_001139008.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNE	ENST00000649488.2	c.53G>T	p.Gly18Val	missense_variant	Exon 2 of 12		NM_000080.4	ENSP00000497829.1
C17orf107	ENST00000381365.4	c.*2224C>A		3_prime_UTR_variant	Exon 3 of 3	2	NM_001145536.2	ENSP00000370770.3

Frequencies

GnomAD3 genomes AF: 0.0319 AC: 4852 AN: 152026 Hom.: 200 Cov.: 32

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

GnomAD2 exomes AF: 0.0487 AC: 12243 AN: 251414 AF XY: 0.0412

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 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.: 35 AF XY: 0.0298 AC XY: 21684 AN XY: 727234

African (AFR) AF: 0.00582 AC: 195 AN: 33480

American (AMR) AF: 0.219 AC: 9781 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00536 AC: 140 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.0114 AC: 982 AN: 86258

European-Finnish (FIN) AF: 0.0339 AC: 1810 AN: 53412

Middle Eastern (MID) AF: 0.0102 AC: 59 AN: 5768

European-Non Finnish (NFE) AF: 0.0280 AC: 31117 AN: 1111992

Other (OTH) AF: 0.0279 AC: 1683 AN: 60396

GnomAD4 genome AF: 0.0319 AC: 4860 AN: 152144 Hom.: 200 Cov.: 32 AF XY: 0.0337 AC XY: 2510 AN XY: 74396

African (AFR) AF: 0.00822 AC: 341 AN: 41506

American (AMR) AF: 0.136 AC: 2078 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5158

South Asian (SAS) AF: 0.00768 AC: 37 AN: 4820

European-Finnish (FIN) AF: 0.0376 AC: 399 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0269 AC: 1827 AN: 67990

Other (OTH) AF: 0.0426 AC: 90 AN: 2114

Alfa AF: 0.0270 Hom.: 562

Bravo AF: 0.0436

TwinsUK AF: 0.0243 AC: 90

ALSPAC AF: 0.0257 AC: 99

ESP6500AA AF: 0.00817 AC: 36

ESP6500EA AF: 0.0223 AC: 192

ExAC AF: 0.0406 AC: 4935

Asia WGS AF: 0.0100 AC: 36 AN: 3478

EpiCase AF: 0.0233

EpiControl AF: 0.0262

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 08, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 19, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

not provided Benign:2

-

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Congenital myasthenic syndrome Benign:2

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 13, 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. -

Congenital myasthenic syndrome 4A Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.61	T
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	N
LIST_S2	Benign	0.37	.;T
MetaRNN	Benign	0.0014	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L
PhyloP100		-0.57
PrimateAI	Uncertain	0.50	T
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	T
GERP RS		1.8
PromoterAI		-0.021	Neutral
Varity_R		0.041
gMVP		0.34
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4790235; hg19: chr17-4806052;