rs28999110

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

Scores

6
12
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 8.14
Variant links:
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
CHRNENM_000080.4 linkuse as main transcriptc.721C>T p.Leu241Phe missense_variant 7/12 ENST00000649488.2 NP_000071.1 Q04844
C17orf107NM_001145536.2 linkuse as main transcriptc.*538G>A 3_prime_UTR_variant 3/3 ENST00000381365.4 NP_001139008.1 Q6ZR85

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CHRNEENST00000649488.2 linkuse as main transcriptc.721C>T p.Leu241Phe missense_variant 7/12 NM_000080.4 ENSP00000497829.1 Q04844
C17orf107ENST00000381365.4 linkuse as main transcriptc.*538G>A 3_prime_UTR_variant 3/32 NM_001145536.2 ENSP00000370770.3 Q6ZR85

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
34
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 submitterclinical testingBaylor GeneticsMay 26, 2022- -
Pathogenic, no assertion criteria providedliterature onlyOMIMJan 01, 1994- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 21, 2021This 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 submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJun 25, 2024Variant 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.44
BayesDel_addAF
Pathogenic
0.30
D
BayesDel_noAF
Pathogenic
0.19
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.76
D;D
Eigen
Pathogenic
0.84
Eigen_PC
Pathogenic
0.75
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.96
.;D
M_CAP
Uncertain
0.20
D
MetaRNN
Pathogenic
0.97
D;D
MetaSVM
Uncertain
0.73
D
MutationAssessor
Uncertain
2.9
M;M
PrimateAI
Uncertain
0.68
T
PROVEAN
Uncertain
-3.7
D;.
REVEL
Pathogenic
0.83
Sift
Uncertain
0.0020
D;.
Sift4G
Uncertain
0.012
D;.
Polyphen
1.0
D;D
Vest4
0.93
MutPred
0.91
Loss of catalytic residue at L241 (P = 0.008);Loss of catalytic residue at L241 (P = 0.008);
MVP
0.92
MPC
0.72
ClinPred
0.99
D
GERP RS
3.9
Varity_R
0.84
gMVP
0.72

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs28999110; hg19: chr17-4804366; API