rs34563587

chr17-4903019-G-Achr17-4903019-G-C

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.45C>T(p.Leu15=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00569 in 1,613,954 control chromosomes in the GnomAD database, including 210 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (100 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (110 hom.)
• Consequence: CHRNE NM_000080.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.0007810
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.26

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:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 17-4903019-G-A is Benign according to our data. Variant chr17-4903019-G-A is described in ClinVar as [Benign]. Clinvar id is 128766.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4903019-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.26 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0653 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNE	NM_000080.4	c.45C>T	p.Leu15=	splice_region_variant, synonymous_variant	1/12	ENST00000649488.2
CHRNE	XM_017024115.2	c.11-256C>T		intron_variant
C17orf107	XR_007065253.1	n.2388+898G>A		intron_variant, non_coding_transcript_variant
C17orf107	XR_007065254.1	n.2388+898G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNE	ENST00000649488.2	c.45C>T	p.Leu15=	splice_region_variant, synonymous_variant	1/12		NM_000080.4	P1
CHRNE	ENST00000649830.1	c.-887-256C>T		intron_variant

Frequencies

GnomAD3 genomes AF: 0.0217 AC: 3296 AN: 151978 Hom.: 100 Cov.: 32

Gnomad AFR AF: 0.0675

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0154

Gnomad ASJ AF: 0.0133

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.00221

Gnomad OTH AF: 0.0287

GnomAD3 exomes AF: 0.00747 AC: 1878 AN: 251398 Hom.: 45 AF XY: 0.00635 AC XY: 863 AN XY: 135892

Gnomad AFR exome AF: 0.0683

Gnomad AMR exome AF: 0.00810

Gnomad ASJ exome AF: 0.0136

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000588

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00232

Gnomad OTH exome AF: 0.0111

GnomAD4 exome AF: 0.00402 AC: 5876 AN: 1461858 Hom.: 110 Cov.: 32 AF XY: 0.00380 AC XY: 2762 AN XY: 727230

Gnomad4 AFR exome AF: 0.0703

Gnomad4 AMR exome AF: 0.00903

Gnomad4 ASJ exome AF: 0.0136

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000916

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.00183

Gnomad4 OTH exome AF: 0.00932

GnomAD4 genome AF: 0.0217 AC: 3302 AN: 152096 Hom.: 100 Cov.: 32 AF XY: 0.0212 AC XY: 1578 AN XY: 74356

Gnomad4 AFR AF: 0.0674

Gnomad4 AMR AF: 0.0154

Gnomad4 ASJ AF: 0.0133

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.00221

Gnomad4 OTH AF: 0.0284

Alfa AF: 0.00557 Hom.: 37

Bravo AF: 0.0248

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.00322

EpiControl AF: 0.00255

ClinVar

Significance: Benign

Submissions summary: Benign:7

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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 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 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. -

Congenital myasthenic syndrome 4A Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Mar 27, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	0.052
Dann	Benign	0.84

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00078
dbscSNV1_RF	Benign	0.0080
SpliceAI score (max)		0.11		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: rs34563587; hg19: chr17-4806314;