rs4790235

chr17-4902757-C-Achr17-4902757-C-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 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. 13/19 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. G18A) 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:9
• Conservation: PhyloP100: -0.570

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

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a signal_peptide (size 19) in uniprot entity ACHE_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_000080.4
• 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	UniProt
CHRNE	NM_000080.4	c.53G>T	p.Gly18Val	missense_variant	2/12	ENST00000649488.2
C17orf107	NM_001145536.2	c.*2224C>A		3_prime_UTR_variant	3/3	ENST00000381365.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNE	ENST00000649488.2	c.53G>T	p.Gly18Val	missense_variant	2/12		NM_000080.4	P1
C17orf107	ENST00000381365.4	c.*2224C>A		3_prime_UTR_variant	3/3	2	NM_001145536.2	A2
CHRNE	ENST00000649830.1	c.-881G>T		5_prime_UTR_variant	2/11

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

GnomAD3 exomes AF: 0.0487 AC: 12243 AN: 251414 Hom.: 1148 AF XY: 0.0412 AC XY: 5599 AN XY: 135888

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

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.: 32 AF XY: 0.0337 AC XY: 2510 AN XY: 74396

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: 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:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	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	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. -

Congenital myasthenic syndrome Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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. -

Congenital myasthenic syndrome 4A Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

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

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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
MetaRNN	Benign	0.0014	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	1.0	P;P
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
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

Other links and lift over

dbSNP: rs4790235; hg19: chr17-4806052;