rs33978919

chr17-4899034-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000080.4(CHRNE):c.1293C>T(p.Ala431=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 1,609,810 control chromosomes in the GnomAD database, including 18,126 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2968 hom., cov: 33)
  • Exomes 𝑓: 0.14 (15158 hom.)
• Consequence: CHRNE NM_000080.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.07

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 17-4899034-G-A is Benign according to our data. Variant chr17-4899034-G-A is described in ClinVar as [Benign]. Clinvar id is 128762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4899034-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.07 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.291 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNE	NM_000080.4	c.1293C>T	p.Ala431=	synonymous_variant	11/12	ENST00000649488.2
CHRNE	XM_017024115.2	c.1257C>T	p.Ala419=	synonymous_variant	12/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNE	ENST00000649488.2	c.1293C>T	p.Ala431=	synonymous_variant	11/12		NM_000080.4	P1
CHRNE	ENST00000649830.1	c.360C>T	p.Ala120=	synonymous_variant	11/11
CHRNE	ENST00000572438.1	n.979C>T		non_coding_transcript_exon_variant	6/7	5
CHRNE	ENST00000652550.1	n.1023C>T		non_coding_transcript_exon_variant	3/4

Frequencies

GnomAD3 genomes AF: 0.182 AC: 27646 AN: 152024 Hom.: 2967 Cov.: 33

Gnomad AFR AF: 0.295

Gnomad AMI AF: 0.150

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.157

Gnomad EAS AF: 0.0595

Gnomad SAS AF: 0.149

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.189

GnomAD3 exomes AF: 0.146 AC: 35202 AN: 240626 Hom.: 2827 AF XY: 0.144 AC XY: 18944 AN XY: 131124

Gnomad AFR exome AF: 0.301

Gnomad AMR exome AF: 0.162

Gnomad ASJ exome AF: 0.147

Gnomad EAS exome AF: 0.0557

Gnomad SAS exome AF: 0.150

Gnomad FIN exome AF: 0.124

Gnomad NFE exome AF: 0.138

Gnomad OTH exome AF: 0.153

GnomAD4 exome AF: 0.140 AC: 204253 AN: 1457666 Hom.: 15158 Cov.: 38 AF XY: 0.140 AC XY: 101479 AN XY: 724782

Gnomad4 AFR exome AF: 0.300

Gnomad4 AMR exome AF: 0.165

Gnomad4 ASJ exome AF: 0.147

Gnomad4 EAS exome AF: 0.0921

Gnomad4 SAS exome AF: 0.150

Gnomad4 FIN exome AF: 0.125

Gnomad4 NFE exome AF: 0.135

Gnomad4 OTH exome AF: 0.148

GnomAD4 genome AF: 0.182 AC: 27679 AN: 152144 Hom.: 2968 Cov.: 33 AF XY: 0.179 AC XY: 13325 AN XY: 74408

Gnomad4 AFR AF: 0.295

Gnomad4 AMR AF: 0.181

Gnomad4 ASJ AF: 0.157

Gnomad4 EAS AF: 0.0598

Gnomad4 SAS AF: 0.149

Gnomad4 FIN AF: 0.115

Gnomad4 NFE AF: 0.137

Gnomad4 OTH AF: 0.186

Alfa AF: 0.156 Hom.: 939

Bravo AF: 0.192

Asia WGS AF: 0.130 AC: 452 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 07, 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	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -

Congenital myasthenic syndrome 4A Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

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 4C Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Congenital myasthenic syndrome 4B Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	5.5
Dann	Benign	0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs33978919; hg19: chr17-4802329; COSMIC: COSV53416641; COSMIC: COSV53416641;