rs786204773
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_000080.4(CHRNE):c.1033-2A>T variant causes a splice acceptor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000326 in 1,533,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000080.4 splice_acceptor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 22 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHRNE | NM_000080.4 | c.1033-2A>T | splice_acceptor_variant | ENST00000649488.2 | |||
CHRNE | XM_017024115.2 | c.997-2A>T | splice_acceptor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHRNE | ENST00000649488.2 | c.1033-2A>T | splice_acceptor_variant | NM_000080.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151992Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000289 AC: 4AN: 1381788Hom.: 0 Cov.: 35 AF XY: 0.00000293 AC XY: 2AN XY: 681866
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 151992Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74244
ClinVar
Submissions by phenotype
Congenital myasthenic syndrome 4A Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 05, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 06, 2023 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 14532324). ClinVar contains an entry for this variant (Variation ID: 189225). Disruption of this splice site has been observed in individual(s) with congenital myasthenic syndrome (PMID: 14532324). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 9 of the CHRNE gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CHRNE are known to be pathogenic (PMID: 22678886). - |
Congenital myasthenic syndrome 4C Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 16, 2014 | The 1033-2A>T variant in CHRNE has not been previously identified in individuals with congenital myasthenic syndrome. Data from large population studies is insufficient to assess the frequency of this variant. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Additionally, other variants at this splice junction (1033-1G>A and 1033-1G>C) have been reported in individuals with congenital myasthenic syndrome (Ohno 2005). In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at