rs372635387
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM1PP5BP4
The NM_000080.4(CHRNE):c.37G>A(p.Gly13Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,613,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. G13G) has been classified as Likely benign.
Frequency
Consequence
NM_000080.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHRNE | NM_000080.4 | c.37G>A | p.Gly13Arg | missense_variant | 1/12 | ENST00000649488.2 | |
CHRNE | XM_017024115.2 | c.11-264G>A | intron_variant | ||||
C17orf107 | XR_007065253.1 | n.2388+906C>T | intron_variant, non_coding_transcript_variant | ||||
C17orf107 | XR_007065254.1 | n.2388+906C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHRNE | ENST00000649488.2 | c.37G>A | p.Gly13Arg | missense_variant | 1/12 | NM_000080.4 | P1 | ||
CHRNE | ENST00000649830.1 | c.-887-264G>A | intron_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152022Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251396Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135892
GnomAD4 exome AF: 0.0000315 AC: 46AN: 1461882Hom.: 0 Cov.: 32 AF XY: 0.0000468 AC XY: 34AN XY: 727246
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152022Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74250
ClinVar
Submissions by phenotype
Congenital myasthenic syndrome 4B Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 1996 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 19, 2019 | This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Congenital myasthenic syndrome 4A Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 09, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 08, 2022 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 13 of the CHRNE protein (p.Gly13Arg). This variant is present in population databases (rs372635387, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical symptoms of autosomal recessive congenital myasthenic syndrome (PMID: 8755487). ClinVar contains an entry for this variant (Variation ID: 18359). 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 not expected to disrupt CHRNE protein function. Experimental studies have shown that this missense change affects CHRNE function (PMID: 8755487). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Congenital myasthenic syndrome 4C Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 19, 2023 | Variant summary: CHRNE c.37G>A (p.Gly13Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251396 control chromosomes. c.37G>A has been reported in the literature in trans along a pathogenic missense in at-least one individual affected with Congenital Myasthenic Syndrome (example, Ohno_1996) . These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in about 40% of normal protein expression when co-expressed with other subunites of acetylcholine receptor in HEK 293 cells (Ohno_1996). The following publication have been ascertained in the context of this evaluation (PMID: 8755487). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=3; Likely pathogenic, n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2023 | - - |
Congenital myasthenic syndrome Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Feb 11, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at