rs765874906
Variant summary
Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_005592.4(MUSK):c.13G>A(p.Val5Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Consequence
NM_005592.4 missense
Scores
Clinical Significance
Conservation
Publications
- congenital myasthenic syndrome 9Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
- fetal akinesia deformation sequence 1Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
- postsynaptic congenital myasthenic syndromeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Likely_benign. The variant received -2 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MUSK | ENST00000374448.9 | c.13G>A | p.Val5Ile | missense_variant | Exon 1 of 15 | 5 | NM_005592.4 | ENSP00000363571.4 | ||
MUSK | ENST00000416899.7 | c.13G>A | p.Val5Ile | missense_variant | Exon 1 of 14 | 5 | ENSP00000393608.3 | |||
MUSK | ENST00000189978.10 | c.13G>A | p.Val5Ile | missense_variant | Exon 1 of 14 | 5 | ENSP00000189978.6 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD2 exomes AF: 0.00000803 AC: 2AN: 249088 AF XY: 0.00000740 show subpopulations
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461296Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4AN XY: 726938 show subpopulations
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Fetal akinesia deformation sequence 1;C4225368:Congenital myasthenic syndrome 9 Uncertain:1
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 5 of the MUSK protein (p.Val5Ile). This variant is present in population databases (rs765874906, gnomAD 0.002%). 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: 1041627). 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 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