rs932032926

chr17-4899325-CCGGGGGGCCTCGGGCGGCGG-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000080.4(CHRNE):c.1072_1091del(p.Pro358GlyfsTer32) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. P358P) has been classified as Likely benign. 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.36

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 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	UniProt
CHRNE	NM_000080.4	c.1072_1091del	p.Pro358GlyfsTer32	frameshift_variant	10/12	ENST00000649488.2
CHRNE	XM_017024115.2	c.1036_1055del	p.Pro346GlyfsTer32	frameshift_variant	11/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNE	ENST00000649488.2	c.1072_1091del	p.Pro358GlyfsTer32	frameshift_variant	10/12		NM_000080.4	P1
CHRNE	ENST00000649830.1	c.139_158del	p.Pro47GlyfsTer32	frameshift_variant	10/11
CHRNE	ENST00000572438.1	n.758_777del		non_coding_transcript_exon_variant	5/7	5
CHRNE	ENST00000652550.1	n.802_821del		non_coding_transcript_exon_variant	2/4

Frequencies

GnomAD3 genomes AF: 0.00000665 AC: 1 AN: 150314 Hom.: 0 Cov.: 32

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: 1 AN: 168526 Hom.: 0 AF XY: 0.0000106 AC XY: 1 AN XY: 94032

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: 9 AN: 1412474 Hom.: 0 AF XY: 0.00000571 AC XY: 4 AN XY: 700108

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: 1 AN: 150314 Hom.: 0 Cov.: 32 AF XY: 0.0000136 AC XY: 1 AN XY: 73414

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital myasthenic syndrome 4A Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 15, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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. -

CHRNE-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs932032926; hg19: chr17-4802620;