rs932032926

Positions:

chr17-4899325-CCGGGGGGCCTCGGGCGGCGG-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000080.4(CHRNE):c.1072_1091delCCGCCGCCCGAGGCCCCCCG(p.Pro358fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000064 in 1,562,788 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000064 ( 0 hom. )

Consequence

CHRNE
NM_000080.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 2.36

Variant links:

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]

CHRNE links:

CHRNE (HGNC:):

CHRNE links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 17-4899325-CCGGGGGGCCTCGGGCGGCGG-C is Pathogenic according to our data. Variant chr17-4899325-CCGGGGGGCCTCGGGCGGCGG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 534252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4899325-CCGGGGGGCCTCGGGCGGCGG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNE	NM_000080.4 linkuse as main transcript	c.1072_1091delCCGCCGCCCGAGGCCCCCCG	p.Pro358fs	frameshift_variant	10/12	ENST00000649488.2	NP_000071.1	Q04844
CHRNE	XM_017024115.2 linkuse as main transcript	c.1036_1055delCCGCCGCCCGAGGCCCCCCG	p.Pro346fs	frameshift_variant	11/13		XP_016879604.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CHRNE	ENST00000649488.2 linkuse as main transcript	c.1072_1091delCCGCCGCCCGAGGCCCCCCG	p.Pro358fs	frameshift_variant	10/12		NM_000080.4	ENSP00000497829.1	Q04844
CHRNE	ENST00000649830.1 linkuse as main transcript	c.139_158delCCGCCGCCCGAGGCCCCCCG	p.Pro47fs	frameshift_variant	10/11			ENSP00000496907.1	A0A3B3IRM1
CHRNE	ENST00000572438.1 linkuse as main transcript	n.758_777delCCGCCGCCCGAGGCCCCCCG		non_coding_transcript_exon_variant	5/7	5
CHRNE	ENST00000652550.1 linkuse as main transcript	n.802_821delCCGCCGCCCGAGGCCCCCCG		non_coding_transcript_exon_variant	2/4

Frequencies

GnomAD3 genomes

AF:

0.00000665

AC:

AN:

150314

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000593

AC:

AN:

168526

Hom.:

AF XY:

0.0000106

AC XY:

AN XY:

94032

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000141

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000637

AC:

AN:

1412474

Hom.:

AF XY:

0.00000571

AC XY:

AN XY:

700108

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000823

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000665

AC:

AN:

150314

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73414

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000148

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital myasthenic syndrome 4A

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change creates a premature translational stop signal (p.Pro358Glyfs*32) in the CHRNE gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHRNE are known to be pathogenic (PMID: 22678886). This variant is present in population databases (no rsID available, gnomAD 0.001%). This variant has not been reported in the literature in individuals affected with CHRNE-related conditions. ClinVar contains an entry for this variant (Variation ID: 534252). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2024	- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 18, 2024

Frameshift variant predicted to result in protein truncation or nonsense-mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge -

CHRNE-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 01, 2024

The CHRNE c.1072_1091del20 variant is predicted to result in a frameshift and premature protein termination (p.Pro358Glyfs*32). To our knowledge, this variant has not been reported in the literature. However, at PreventionGenetics we have observed this variant in the homozygous state in two other patients presenting with myasthenic syndrome phenotypes. This variant is reported in 0.0014% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in CHRNE are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Congenital myasthenic syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

Dec 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over