rs28929768
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PP3_StrongPP5
The NM_000080.4(CHRNE):āc.293T>Cā(p.Leu98Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L98L) has been classified as Likely benign.
Frequency
Consequence
NM_000080.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHRNE | NM_000080.4 | c.293T>C | p.Leu98Pro | missense_variant | 4/12 | ENST00000649488.2 | |
C17orf107 | NM_001145536.2 | c.*1735A>G | 3_prime_UTR_variant | 3/3 | ENST00000381365.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHRNE | ENST00000649488.2 | c.293T>C | p.Leu98Pro | missense_variant | 4/12 | NM_000080.4 | P1 | ||
C17orf107 | ENST00000381365.4 | c.*1735A>G | 3_prime_UTR_variant | 3/3 | 2 | NM_001145536.2 | A2 | ||
CHRNE | ENST00000649830.1 | c.-641T>C | 5_prime_UTR_variant | 4/11 | |||||
CHRNE | ENST00000575637.1 | n.114T>C | non_coding_transcript_exon_variant | 3/6 | 3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251486Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135920
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461890Hom.: 0 Cov.: 35 AF XY: 0.0000138 AC XY: 10AN XY: 727246
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Congenital myasthenic syndrome 4A Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Lifecell International Pvt. Ltd | - | A Heterozygous Missense variant c.293T>C in Exon 4 of the CHRNE gene that results in the amino acid substitution p.Leu98Pro was identified. The observed variant allele frequency of 0.00002/0.00 % in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Likely Pathogenic (ClinVar ID: 534249). This missense change has been observed in individual(s) with congenital myasthenic syndrome (Selvam P et al., 2018). Based on the above evidence this variant has been classified as Likely Pathogenic according to the ACMG guidelines. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 23, 2022 | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 98 of the CHRNE protein (p.Leu98Pro). This variant is present in population databases (rs28929768, gnomAD 0.01%). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CHRNE protein function. ClinVar contains an entry for this variant (Variation ID: 534249). This missense change has been observed in individual(s) with autosomal recessive congenital myasthenic syndrome (PMID: 30124556; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 19, 2024 | - - |
Congenital myasthenic syndrome 4C Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust | Mar 23, 2023 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 18, 2021 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 12141316, 19153382, 30124556) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at