chr17-4902679-T-TC
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000080.4(CHRNE):c.130_131insG(p.Glu44GlyfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000446 in 1,613,646 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. E44E) 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.130_131insG | p.Glu44GlyfsTer3 | frameshift_variant | 2/12 | ENST00000649488.2 | |
C17orf107 | NM_001145536.2 | c.*2149dup | 3_prime_UTR_variant | 3/3 | ENST00000381365.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHRNE | ENST00000649488.2 | c.130_131insG | p.Glu44GlyfsTer3 | frameshift_variant | 2/12 | NM_000080.4 | P1 | ||
C17orf107 | ENST00000381365.4 | c.*2149dup | 3_prime_UTR_variant | 3/3 | 2 | NM_001145536.2 | A2 | ||
CHRNE | ENST00000649830.1 | c.-804_-803insG | 5_prime_UTR_variant | 2/11 | |||||
CHRNE | ENST00000575637.1 | upstream_gene_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000725 AC: 11AN: 151772Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000103 AC: 26AN: 251458Hom.: 0 AF XY: 0.000110 AC XY: 15AN XY: 135916
GnomAD4 exome AF: 0.0000417 AC: 61AN: 1461874Hom.: 0 Cov.: 35 AF XY: 0.0000399 AC XY: 29AN XY: 727236
GnomAD4 genome ? AF: 0.0000725 AC: 11AN: 151772Hom.: 0 Cov.: 32 AF XY: 0.0000674 AC XY: 5AN XY: 74138
ClinVar
Submissions by phenotype
Congenital myasthenic syndrome 4C;C4225369:Congenital myasthenic syndrome 4B;C4225413:Congenital myasthenic syndrome 4A Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 26, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Mar 11, 2022 | PVS1, PM2, PM3 - |
Pathogenic, criteria provided, single submitter | clinical testing | Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics | Nov 27, 2021 | A homozygous single base pair duplication in exon 2 of the CHRNE gene that results in a frameshift and premature truncation of the protein 3 amino acids down stream to codon 44 was detected. This variant has not been reported in the 1000 genomes database and has a minor allele frequency of 0.007% in the gnomAD. The observed variation has previously been reported in patients affected with congenital myasthenic syndrome. - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 04, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 16, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 06, 2021 | Published functional studies demonstrate impaired a-bgt binding to the acetylcholine receptor (Ohno et al., 1998); 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; This variant is associated with the following publications: (PMID: 9708546, 20301347, 29383513, 31773638) - |
Congenital myasthenic syndrome Pathogenic:2Other:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 17, 2018 | The p.Glu44GlyfsX3 variant in CHRNE is a well-established pathogenic variant and has been reported in >20 Spanish and Portuguese individuals with congenital mya sthenic syndrome (Ohno 1998, Mihaylova 2010, Natera-de Benito 2017, Estephan 201 8). It has been reported as Pathogenic in ClinVar (Variation ID 243030), and has been identified in 0.06% (20/33580) of Latino chromosomes by the Genome Aggrega tion Database (gnomAD, http://gnomad.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enough to be consi stent with a recessive carrier frequency. This variant is predicted to cause a f rameshift, which alters the protein?s amino acid sequence beginning at position 44 and leads to a premature termination codon 3 amino acids downstream. This alt eration is then predicted to lead to a truncated or absent protein. In summary, this variant meets criteria to be classified as pathogenic for congenital myasth enic syndrome in an autosomal recessive manner. ACMG/AMP Criteria applied: PVS1, PM3_VeryStrong, PS3_Supporting. - |
Congenital myasthenic syndrome 4A Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | This sequence change creates a premature translational stop signal (p.Glu44Glyfs*3) 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 (rs762368691, gnomAD 0.06%). This premature translational stop signal has been observed in individuals with autosomal recessive congenital myasthenic syndrome (PMID: 9708546). This variant is also known as epsilon70insG. ClinVar contains an entry for this variant (Variation ID: 243030). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 11, 2023 | - - |
Myasthenic syndrome, slow-channel congenital Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | DASA | Jan 05, 2022 | The c.130dupG;p.(Glu44Glyfs*3) is a null frameshift variant (NMD) in the CHRNE gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevantexon to the transcript -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 243030; PMID: 20301347; 9708546; 22678886; 29383513;29054425; 20562457; 9708546PS4. The variant is present at low allele frequencies population databases (rs762368691– gnomAD 0.007248%; ABraOM 0.000854 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Glu44Glyfs*3) was detected in trans with a pathogenic variant (PMID: 29383513, 29054425) - PM3. The variant co-segregated with disease in multiple affected family members (PMID: 29383513) - PP1_moderate. In summary, the currently available evidence indicates that the variant is pathogenic. - |
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