rs551520537
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_005592.4(MUSK):c.2443G>A(p.Val815Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000822 in 1,460,432 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V815L) has been classified as Likely benign.
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.2443G>A | p.Val815Met | missense_variant | 15/15 | ENST00000374448.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MUSK | ENST00000374448.9 | c.2443G>A | p.Val815Met | missense_variant | 15/15 | 5 | NM_005592.4 | P4 | |
MUSK | ENST00000416899.7 | c.2419G>A | p.Val807Met | missense_variant | 14/14 | 5 | A1 | ||
MUSK | ENST00000189978.10 | c.2185G>A | p.Val729Met | missense_variant | 14/14 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000242 AC: 6AN: 248308Hom.: 0 AF XY: 0.0000297 AC XY: 4AN XY: 134596
GnomAD4 exome AF: 0.00000822 AC: 12AN: 1460432Hom.: 0 Cov.: 32 AF XY: 0.00000964 AC XY: 7AN XY: 726262
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Fetal akinesia deformation sequence 1;C4225368:Congenital myasthenic syndrome 9 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 01, 2021 | This sequence change replaces valine with methionine at codon 815 of the MUSK protein (p.Val815Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs551520537, ExAC 0.02%). This variant has not been reported in the literature in individuals affected with MUSK-related conditions. 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