17-4899326-CG-CGG
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000080.4(CHRNE):c.1090_1091insC(p.Arg364ProfsTer33) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000514 in 1,557,266 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R364R) 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.1090_1091insC | p.Arg364ProfsTer33 | frameshift_variant | 10/12 | ENST00000649488.2 | |
CHRNE | XM_017024115.2 | c.1054_1055insC | p.Arg352ProfsTer33 | frameshift_variant | 11/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHRNE | ENST00000649488.2 | c.1090_1091insC | p.Arg364ProfsTer33 | frameshift_variant | 10/12 | NM_000080.4 | P1 | ||
CHRNE | ENST00000649830.1 | c.157_158insC | p.Arg53ProfsTer33 | frameshift_variant | 10/11 | ||||
CHRNE | ENST00000572438.1 | n.776_777insC | non_coding_transcript_exon_variant | 5/7 | 5 | ||||
CHRNE | ENST00000652550.1 | n.820_821insC | non_coding_transcript_exon_variant | 2/4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000661 AC: 1AN: 151352Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000498 AC: 7AN: 1405914Hom.: 0 Cov.: 35 AF XY: 0.00000574 AC XY: 4AN XY: 696292
GnomAD4 genome ? AF: 0.00000661 AC: 1AN: 151352Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 73944
ClinVar
Submissions by phenotype
Congenital myasthenic syndrome 4A Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Apr 29, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 17, 2023 | This sequence change creates a premature translational stop signal (p.Arg364Profs*33) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 434765). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 05, 2019 | - - |
CHRNE-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 24, 2023 | The CHRNE c.1090dupC variant is predicted to result in a frameshift and premature protein termination (p.Arg364Profs*33). To our knowledge, this variant has not been reported in the literature or a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At PreventionGenetics, we have observed the c.1090dupC variant in the compound heterozygous and homozygous state in individuals being testing for congenital myasthenic syndrome (internal data). Frameshift variants in CHRNE are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Congenital myasthenic syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 22, 2016 | - - |
Abnormality of the musculature Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Kariminejad - Najmabadi Pathology & Genetics Center | Jul 10, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at