rs763258280
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_StrongPP5
The NM_000080.4(CHRNE):c.1327del(p.Glu443LysfsTer64) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000596 in 1,577,704 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. E443E) has been classified as Likely benign.
Frequency
Consequence
NM_000080.4 frameshift, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHRNE | NM_000080.4 | c.1327del | p.Glu443LysfsTer64 | frameshift_variant, splice_region_variant | 12/12 | ENST00000649488.2 | |
CHRNE | XM_017024115.2 | c.1291del | p.Glu431LysfsTer64 | frameshift_variant, splice_region_variant | 13/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHRNE | ENST00000649488.2 | c.1327del | p.Glu443LysfsTer64 | frameshift_variant, splice_region_variant | 12/12 | NM_000080.4 | P1 | ||
CHRNE | ENST00000649830.1 | c.503del | p.Gly168GlufsTer52 | frameshift_variant | 11/11 | ||||
CHRNE | ENST00000572438.1 | n.1013del | splice_region_variant, non_coding_transcript_exon_variant | 7/7 | 5 | ||||
CHRNE | ENST00000652550.1 | n.1057-4del | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152040Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000128 AC: 24AN: 188070Hom.: 0 AF XY: 0.000179 AC XY: 18AN XY: 100644
GnomAD4 exome AF: 0.0000652 AC: 93AN: 1425664Hom.: 0 Cov.: 34 AF XY: 0.0000921 AC XY: 65AN XY: 705750
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152040Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74256
ClinVar
Submissions by phenotype
Congenital myasthenic syndrome 4A Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Nov 30, 2023 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Zotz-Klimas Genetics Lab, MVZ Zotz Klimas | Oct 30, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics | Feb 07, 2022 | A homozygous single base pair deletion c.1267delG in exon 12 of the CHRNE gene that results in a frameshift and premature truncation of the protein 64 amino acids downstream to codon 443 (p.Glu443LysfsTer64) was detected. The observed variation (c.1267delG) has previously been reported in patients affected with congenital myasthenic syndrome and the variant has been classified as pathogenic by ClinVar database. This variant has not been reported in the 1000 genomes database and has a minor allele frequency of 0.15% in the gnomAD . The reference region is conserved across species. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 24, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The frameshift variant c.1327del(p.Glu443LysfsTer64) in CHRNE gene has been observed in individual(s) with autosomal recessive congenital myasthenic syndrome (Natera-de Benito D et.al.,2016). Experimental studies have shown that this frameshift affects CHRNE function (Yang Y et.al.,2014). This variant has been reported to the ClinVar database as Pathogenic. The p.Glu443LysfsTer64 variant is reported with allele frequency of 0.01% in gnomAD exomes and novel in 1000 Genomes. This variant causes a frameshift starting with codon Glutamic Acid 443, changes this amino acid to Lysine residue, and creates a premature Stop codon at position 64 of the new reading frame, denoted p.Glu443LysfsTer64. This variant is predicted to cause loss of normal protein function. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 25, 2023 | This sequence change results in a frameshift in the CHRNE gene (p.Glu443Lysfs*64). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 51 amino acid(s) of the CHRNE protein and extend the protein by 12 additional amino acid residues. This variant is present in population databases (rs763258280, gnomAD 0.09%). This frameshift has been observed in individual(s) with autosomal recessive congenital myasthenic syndrome (PMID: 9668239, 10496269, 10514102, 10534268, 27634344). It is commonly reported in individuals of Roma ancestry (PMID: 15322984, 15367858). This variant is also known as c.1267delG. ClinVar contains an entry for this variant (Variation ID: 243031). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this frameshift affects CHRNE function (PMID: 10514102). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 10, 2021 | Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 51 amino acids are lost and replaced with 63 incorrect amino acids; This variant is associated with the following publications: (PMID: 10514102, 10496269, 15367858, 15322984, 10534268, 9668239, 27634344, 28464723, 29056292, 29054425, 30369941, 31589614, 33193787, 34426522, 34008892, 32070632, 31407473) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2020 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 30, 2016 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Congenital myasthenic syndrome 4C Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 01, 2017 | This mutation has been previously reported as disease-causing and was found twice in our laboratory in a homozygous state in individuals with myasthenia. One was as 8-year-old male with congenital myasthenia, with a similarly affected sister (not tested); other was a 15-year-old female with myasthenia gravis, mild intellectual disability. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2004 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The frame shift c.1327del (p.Glu443LysfsTer64) variant in CHRNE gene has been reported previously in homozygous state associated with congenital myasthenia syndrome. This variant has been reported to segregate with autosomal recessive congenital myasthenic syndrome (CMS) in many families. This variant is predicted to cause loss of normal protein function, as the last 51 amino acids are lost and replaced with 63 incorrect amino acids (Croxen, R et al, Natera-de Benito, D et al.). This variant is reported with the allele frequency 0.01% in the gnomAD and novel in 1000 genome database. This variant has been reported to the ClinVar database as Pathogenic. This variant causes a frameshift starting with codon Glutamic Acid 443, changes this amino acid to Lysine residue, and creates a premature Stop codon at position 64 of the new reading frame, denoted p.Glu443LysfsTer64. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Oct 25, 2017 | - - |
Congenital myasthenic syndrome 4B Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | Mar 01, 2023 | The frame shift c.1327del (p.Glu443LysfsTer64) variant has been reported in homozygous and compound heterozygous state in individuals affected with affected with Congenital Myasthenic Syndrome (Parvizi Omran S et al. 2019; Durmus H et al. 2018). Experimental studies have shown that this frameshift affects CHRNE function (Croxen R et al. 1999). The p.Glu443LysfsTer64 variant has allele frequency 0.01% in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submiters). This variant causes a frameshift starting with codon Glutamic Acid 443, changes this amino acid to Lysine residue, and creates a premature Stop codon at position 64 of the new reading frame, denoted p.Glu443LysfsTer64. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Feb 23, 2023 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.013%). This variant was predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. Multiple pathogenic variants are reported downstream of the variant. This homozygous variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000243031 / PMID: 9668239). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | May 03, 2020 | - - |
Congenital myasthenic syndrome Pathogenic:1Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Congenital myasthenic syndrome 4C;C4225369:Congenital myasthenic syndrome 4B;C4225413:Congenital myasthenic syndrome 4A Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Suma Genomics | - | - - |
Congenital myasthenic syndrome 1A Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The frameshift variant c.1327del (p.Glu443LysfsTer64) in CHRNE gene has been reported to segregate with autosomal recessive congenital myasthenic syndrome (CMS) in many families (Natera-de Benito D et.al.,2016). It is a common cause of autosomal recessive CMS in several populations, and has been reported to be a founder mutation in the Roma population (Hantaï D et.al.,2004).This variant has been reported to the ClinVar database as Pathogenic. The p.Glu443LysfsTer64 variant is reported with the allele frequency 0.01276% in gnomAD exomes and novel in 1000 Genomes. This variant causes a frameshift starting with codon Glutamic Acid 443, changes this amino acid to Lysine residue, and creates a premature Stop codon at position 64 of the new reading frame, denoted p.Glu443LysfsTer64. This variant is predicted to cause loss of normal protein function. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at