rs370079610
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_005592.4(MUSK):c.2300G>A(p.Arg767His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000075 in 1,613,968 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 (★★).
Frequency
Consequence
NM_005592.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MUSK | ENST00000374448.9 | c.2300G>A | p.Arg767His | missense_variant | Exon 15 of 15 | 5 | NM_005592.4 | ENSP00000363571.4 | ||
MUSK | ENST00000416899.7 | c.2276G>A | p.Arg759His | missense_variant | Exon 14 of 14 | 5 | ENSP00000393608.3 | |||
MUSK | ENST00000189978.10 | c.2042G>A | p.Arg681His | missense_variant | Exon 14 of 14 | 5 | ENSP00000189978.6 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152140Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000161 AC: 4AN: 249012Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135084
GnomAD4 exome AF: 0.0000787 AC: 115AN: 1461710Hom.: 0 Cov.: 32 AF XY: 0.0000646 AC XY: 47AN XY: 727138
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152258Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74430
ClinVar
Submissions by phenotype
not specified Uncertain:1
The R767H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R767H variant was not observed with any significant frequency in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The R767H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -
Inborn genetic diseases Uncertain:1
The c.2300G>A (p.R767H) alteration is located in exon 15 (coding exon 15) of the MUSK gene. This alteration results from a G to A substitution at nucleotide position 2300, causing the arginine (R) at amino acid position 767 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Fetal akinesia deformation sequence 1;C4225368:Congenital myasthenic syndrome 9 Uncertain:1
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 767 of the MUSK protein (p.Arg767His). This variant is present in population databases (rs370079610, gnomAD 0.006%). 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: 372415). 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