rs2075763

Positions:

• chr17-4899390-G-A

Variant summary

Our verdict is Benign. Variant got -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, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001104
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.242

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 -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 id is 128761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4899390-G-A is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
CHRNE	NM_000080.4	c.1033-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000649488.2	NP_000071.1
CHRNE	XM_017024115.2	c.997-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			XP_016879604.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNE	ENST00000649488.2	c.1033-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_000080.4	ENSP00000497829	P1

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

GnomAD3 exomes AF: 0.0958 AC: 12701 AN: 132610 Hom.: 822 AF XY: 0.0929 AC XY: 6764 AN XY: 72800

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 SAS exome AF: 0.0944

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

Gnomad4 AFR exome AF: 0.0388

Gnomad4 AMR exome AF: 0.140

Gnomad4 ASJ exome AF: 0.0658

Gnomad4 EAS exome AF: 0.212

Gnomad4 SAS exome AF: 0.0961

Gnomad4 FIN exome AF: 0.0743

Gnomad4 NFE exome AF: 0.0598

Gnomad4 OTH exome AF: 0.0788

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

Gnomad4 AFR AF: 0.0421

Gnomad4 AMR AF: 0.123

Gnomad4 ASJ AF: 0.0559

Gnomad4 EAS AF: 0.227

Gnomad4 SAS AF: 0.0959

Gnomad4 FIN AF: 0.0737

Gnomad4 NFE AF: 0.0600

Gnomad4 OTH AF: 0.0615

Alfa AF: 0.0631 Hom.: 66

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

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
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	PreventionGenetics, part of Exact Sciences	-	- -

Congenital myasthenic syndrome 4A Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

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 12, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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	-0.57
CADD	Benign	2.4
DANN	Benign	0.95

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

Publications

LitVar

Other links and lift over

dbSNP: rs2075763; hg19: chr17-4802685;