rs373304727
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_005592.4(MUSK):āc.557G>Cā(p.Gly186Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000533 in 1,612,906 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 Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G186E) has been classified as Uncertain significance.
Frequency
Consequence
NM_005592.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MUSK | NM_005592.4 | c.557G>C | p.Gly186Ala | missense_variant | 5/15 | ENST00000374448.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MUSK | ENST00000374448.9 | c.557G>C | p.Gly186Ala | missense_variant | 5/15 | 5 | NM_005592.4 | P4 | |
MUSK | ENST00000416899.7 | c.557G>C | p.Gly186Ala | missense_variant | 5/14 | 5 | A1 | ||
MUSK | ENST00000189978.10 | c.557G>C | p.Gly186Ala | missense_variant | 5/14 | 5 | |||
MUSK | ENST00000374439.1 | c.251G>C | p.Gly84Ala | missense_variant | 3/4 | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152070Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000442 AC: 11AN: 248594Hom.: 0 AF XY: 0.0000371 AC XY: 5AN XY: 134896
GnomAD4 exome AF: 0.0000575 AC: 84AN: 1460836Hom.: 0 Cov.: 31 AF XY: 0.0000564 AC XY: 41AN XY: 726742
GnomAD4 genome AF: 0.0000132 AC: 2AN: 152070Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74270
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 24, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 21, 2017 | The G186A variant in the MUSK gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The G186A variant is observed in 3/11576 (0.026%) alleles from individuals of Latino background in the ExAC dataset (Lek et al., 2016). The G186A variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret G186A as a variant of uncertain significance. - |
Fetal akinesia deformation sequence 1;C4225368:Congenital myasthenic syndrome 9 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 23, 2022 | This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 186 of the MUSK protein (p.Gly186Ala). This variant is present in population databases (rs373304727, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with MUSK-related conditions. ClinVar contains an entry for this variant (Variation ID: 432807). 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 MUSK protein function. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at