rs879255562
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000080.4(CHRNE):βc.971delβ(p.Ile324ThrfsTer61) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000274 in 1,604,576 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. I324I) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000080.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHRNE | NM_000080.4 | c.971del | p.Ile324ThrfsTer61 | frameshift_variant | 9/12 | ENST00000649488.2 | |
C17orf107 | NM_001145536.2 | upstream_gene_variant | ENST00000381365.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHRNE | ENST00000649488.2 | c.971del | p.Ile324ThrfsTer61 | frameshift_variant | 9/12 | NM_000080.4 | P1 | ||
C17orf107 | ENST00000381365.4 | upstream_gene_variant | 2 | NM_001145536.2 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152202Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.0000275 AC: 40AN: 1452374Hom.: 0 Cov.: 34 AF XY: 0.0000250 AC XY: 18AN XY: 721338
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152202Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74356
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 20, 2023 | Using alternate nomenclature (c.911delT), reported in association with autosomal recessive congenital myasthenia syndrome when in trans with another disease-causing variant (Sieb et al., 2000; Burke et al., 2004; Muller et al., 2005); Expression of variant in HEK 293 cells showed decreased cell surface expression of the protein (Burke et al., 2004); 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); This variant is associated with the following publications: (PMID: 11030414, 15145336, 16087917, 9443457, 29395675) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 05, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 24, 2019 | - - |
Congenital myasthenic syndrome 4A Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | This sequence change creates a premature translational stop signal (p.Ile324Thrfs*61) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with autosomal recessive congenital myasthenic syndromes (PMID: 11030414, 16087917). This variant is also known as 911delT. ClinVar contains an entry for this variant (Variation ID: 18348). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 20, 2024 | - - |
Congenital myasthenic syndrome 4C Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 09, 2005 | - - |
Congenital myasthenic syndrome 4B Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Aug 16, 2022 | - - |
Congenital myasthenic syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at