rs28999110
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000080.4(CHRNE):c.721C>T(p.Leu241Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Consequence
CHRNE
NM_000080.4 missense
NM_000080.4 missense
Scores
6
12
1
Clinical Significance
Conservation
PhyloP100: 8.14
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]
C17orf107 (HGNC:37238): (chromosome 17 open reading frame 107)
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.974
PP5
Variant 17-4901071-G-A is Pathogenic according to our data. Variant chr17-4901071-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 18352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4901071-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CHRNE | NM_000080.4 | c.721C>T | p.Leu241Phe | missense_variant | 7/12 | ENST00000649488.2 | NP_000071.1 | |
C17orf107 | NM_001145536.2 | c.*538G>A | 3_prime_UTR_variant | 3/3 | ENST00000381365.4 | NP_001139008.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CHRNE | ENST00000649488.2 | c.721C>T | p.Leu241Phe | missense_variant | 7/12 | NM_000080.4 | ENSP00000497829.1 | |||
C17orf107 | ENST00000381365.4 | c.*538G>A | 3_prime_UTR_variant | 3/3 | 2 | NM_001145536.2 | ENSP00000370770.3 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 34
GnomAD4 exome
Cov.:
34
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Congenital myasthenic syndrome 4A Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 26, 2022 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1994 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 21, 2021 | This sequence change replaces leucine with phenylalanine at codon 241 of the CHRNE protein (p.Leu241Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of autosomal dominant congenital myasthenic syndrome (PMID: 12141316, 30542963). ClinVar contains an entry for this variant (Variation ID: 18352). This variant is also described as L221F in the literature. 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. Experimental studies have shown that this variant affects CHRNE protein function (PMID: 12141316, 22178625). For these reasons, this variant has been classified as Pathogenic. - |
Congenital myasthenic syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 25, 2024 | Variant summary: CHRNE c.721C>T (p.Leu241Phe) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250002 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.721C>T has been reported in the literature in multiple heterozygous individuals affected with slow-channel congenital myasthenic syndromes (Croxen_2002, Angelini_2019). Two publications report experimental evidence evaluating an impact on protein function. In one study in transient transfection into HEK293 cells, patch clamping showed 2.4-fold slow in time constant of decay of the synaptic current (Croxen_2002). In a mouse model carrying this missense variant, prolonged endplate currents was observed that is associated with moderate reduced muscle strength and tetanic fade, calcium and intracellular vesicle accumulation as well as junctional fold loss and organelle degeneration, and a remodeling of neuromuscular junctions (Chevessier_2012). The following publications have been ascertained in the context of this evaluation (PMID: 30542963, 22178625, 12141316). ClinVar contains an entry for this variant (Variation ID: 18352). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.
REVEL
Pathogenic
Sift
Uncertain
D;.
Sift4G
Uncertain
D;.
Polyphen
D;D
Vest4
MutPred
Loss of catalytic residue at L241 (P = 0.008);Loss of catalytic residue at L241 (P = 0.008);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at