rs2075763

Variant names:

• chr17-4899390-G-A
• rs2075763
• NM_000080.4:c.1033-6C>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.1033-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0687 in 1,533,868 control chromosomes in the GnomAD database, including 4,444 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.069 (492 hom., cov: 33)
  • Exomes 𝑓: 0.069 (3952 hom.)
• Consequence: CHRNE NM_000080.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001104
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.242
• Publications: 9 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 (BayesDel_noAF=-0.57).
• BP6: Variant 17-4899390-G-A is Benign according to our data. Variant chr17-4899390-G-A is described in ClinVar as Benign. ClinVar VariationId is 128761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.216 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNE	NM_000080.4	c.1033-6C>T		splice_region_variant, intron_variant	Intron 9 of 11	ENST00000649488.2	NP_000071.1
C17orf107	NM_001145536.2	c.-373G>A		upstream_gene_variant		ENST00000381365.4	NP_001139008.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNE	ENST00000649488.2	c.1033-6C>T		splice_region_variant, intron_variant	Intron 9 of 11		NM_000080.4	ENSP00000497829.1
C17orf107	ENST00000381365.4	c.-373G>A		upstream_gene_variant		2	NM_001145536.2	ENSP00000370770.3

Frequencies

GnomAD3 genomes AF: 0.0691 AC: 10502 AN: 152034 Hom.: 493 Cov.: 33

Gnomad AFR AF: 0.0421

Gnomad AMI AF: 0.0650

Gnomad AMR AF: 0.122

Gnomad ASJ AF: 0.0559

Gnomad EAS AF: 0.228

Gnomad SAS AF: 0.0964

Gnomad FIN AF: 0.0737

Gnomad MID AF: 0.0478

Gnomad NFE AF: 0.0600

Gnomad OTH AF: 0.0631

GnomAD2 exomes AF: 0.0958 AC: 12701 AN: 132610 AF XY: 0.0929

Gnomad AFR exome AF: 0.0414

Gnomad AMR exome AF: 0.144

Gnomad ASJ exome AF: 0.0643

Gnomad EAS exome AF: 0.238

Gnomad FIN exome AF: 0.0825

Gnomad NFE exome AF: 0.0588

Gnomad OTH exome AF: 0.0867

GnomAD4 exome AF: 0.0686 AC: 94822 AN: 1381718 Hom.: 3952 Cov.: 35 AF XY: 0.0692 AC XY: 47159 AN XY: 681746

African (AFR) AF: 0.0388 AC: 1212 AN: 31258

American (AMR) AF: 0.140 AC: 4717 AN: 33804

Ashkenazi Jewish (ASJ) AF: 0.0658 AC: 1608 AN: 24424

East Asian (EAS) AF: 0.212 AC: 7598 AN: 35908

South Asian (SAS) AF: 0.0961 AC: 7578 AN: 78822

European-Finnish (FIN) AF: 0.0743 AC: 2938 AN: 39538

Middle Eastern (MID) AF: 0.0710 AC: 331 AN: 4664

European-Non Finnish (NFE) AF: 0.0598 AC: 64320 AN: 1075918

Other (OTH) AF: 0.0788 AC: 4520 AN: 57382

GnomAD4 genome AF: 0.0690 AC: 10503 AN: 152150 Hom.: 492 Cov.: 33 AF XY: 0.0715 AC XY: 5318 AN XY: 74374

African (AFR) AF: 0.0421 AC: 1748 AN: 41562

American (AMR) AF: 0.123 AC: 1875 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0559 AC: 194 AN: 3472

East Asian (EAS) AF: 0.227 AC: 1164 AN: 5128

South Asian (SAS) AF: 0.0959 AC: 463 AN: 4828

European-Finnish (FIN) AF: 0.0737 AC: 779 AN: 10568

Middle Eastern (MID) AF: 0.0445 AC: 13 AN: 292

European-Non Finnish (NFE) AF: 0.0600 AC: 4078 AN: 67972

Other (OTH) AF: 0.0615 AC: 130 AN: 2114

Alfa AF: 0.0631 Hom.: 67

Bravo AF: 0.0722

Asia WGS AF: 0.127 AC: 443 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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. -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital myasthenic syndrome 4A Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital myasthenic 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. -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Congenital myasthenic syndrome 4C Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Congenital myasthenic syndrome 4B Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	2.4
DANN	Benign	0.95
PhyloP100		-0.24
PromoterAI		0.021	Neutral
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.016
SpliceAI score (max)		0.020		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: rs2075763; hg19: chr17-4802685;