rs755303686
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Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PP3_StrongPP5_Very_Strong
The NM_000080.4(CHRNE):c.1033-1G>C variant causes a splice acceptor change. The variant allele was found at a frequency of 0.0000196 in 1,533,896 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
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000020 ( 0 hom. )
Consequence
CHRNE
NM_000080.4 splice_acceptor
NM_000080.4 splice_acceptor
Scores
1
2
4
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 3.71
Genes affected
CHRNE (HGNC:1966): (cholinergic receptor nicotinic epsilon subunit) Acetylcholine receptors at mature mammalian neuromuscular junctions are pentameric protein complexes composed of four subunits in the ratio of two alpha subunits to one beta, one epsilon, and one delta subunit. The acetylcholine receptor changes subunit composition shortly after birth when the epsilon subunit replaces the gamma subunit seen in embryonic receptors. Mutations in the epsilon subunit are associated with congenital myasthenic syndrome. [provided by RefSeq, Sep 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 20 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 17-4899385-C-G is Pathogenic according to our data. Variant chr17-4899385-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 420092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4899385-C-G is described in Lovd as [Pathogenic]. Variant chr17-4899385-C-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHRNE | NM_000080.4 | c.1033-1G>C | splice_acceptor_variant | ENST00000649488.2 | |||
CHRNE | XM_017024115.2 | c.997-1G>C | splice_acceptor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHRNE | ENST00000649488.2 | c.1033-1G>C | splice_acceptor_variant | NM_000080.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152088Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000754 AC: 1AN: 132702Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 72848
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GnomAD4 exome AF: 0.0000203 AC: 28AN: 1381808Hom.: 0 Cov.: 35 AF XY: 0.0000161 AC XY: 11AN XY: 681872
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GnomAD4 genome AF: 0.0000132 AC: 2AN: 152088Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74298
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 30, 2022 | PM2, PVS1_strong - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 21, 2017 | The c.1033-1G>C variant in the CHRNE gene has been reported previously in association with congenital myasthenic syndrome (Stenson et al., 2014). This splice site variant destroys the canonical splice acceptor site in intron 9. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.1033-1G>C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.1033-1G>C as a pathogenic variant. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 21, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | May 15, 2017 | - - |
Congenital myasthenic syndrome 4A Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | 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). 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. Disruption of this splice site has been observed in individual(s) with clinical features of autosomal recessive congenital myasthenic syndrome (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 420092). 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 06, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Benign
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D
GERP RS
Splicing
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Calibrated prediction
Score
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: -13
DS_AL_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at