rs779042240
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_005592.4(MUSK):c.2014C>T(p.Pro672Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000889 in 1,461,708 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000089 ( 0 hom. )
Consequence
MUSK
NM_005592.4 missense
NM_005592.4 missense
Scores
3
8
8
Clinical Significance
Conservation
PhyloP100: 6.09
Genes affected
MUSK (HGNC:7525): (muscle associated receptor tyrosine kinase) This gene encodes a muscle-specific tyrosine kinase receptor. The encoded protein may play a role in clustering of the acetylcholine receptor in the postsynaptic neuromuscular junction. Mutations in this gene have been associated with congenital myasthenic syndrome. Alternatively spliced transcript variants have been described.[provided by RefSeq, Oct 2009]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MUSK | NM_005592.4 | c.2014C>T | p.Pro672Ser | missense_variant | 15/15 | ENST00000374448.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MUSK | ENST00000374448.9 | c.2014C>T | p.Pro672Ser | missense_variant | 15/15 | 5 | NM_005592.4 | P4 | |
MUSK | ENST00000416899.7 | c.1990C>T | p.Pro664Ser | missense_variant | 14/14 | 5 | A1 | ||
MUSK | ENST00000189978.10 | c.1756C>T | p.Pro586Ser | missense_variant | 14/14 | 5 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.0000241 AC: 6AN: 249258Hom.: 0 AF XY: 0.0000296 AC XY: 4AN XY: 135212
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GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461708Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10AN XY: 727136
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GnomAD4 genome Cov.: 32
GnomAD4 genome
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32
ExAC
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3
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 03, 2019 | - - |
Fetal akinesia deformation sequence 1;C4225368:Congenital myasthenic syndrome 9 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 03, 2022 | This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 672 of the MUSK protein (p.Pro672Ser). This variant is present in population databases (rs779042240, gnomAD 0.02%). 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: 542741). 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Pathogenic
DEOGEN2
Uncertain
T;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Benign
L;.;.;.
MutationTaster
Benign
D;D;D
PrimateAI
Benign
T
PROVEAN
Pathogenic
D;.;.;.
REVEL
Benign
Sift
Uncertain
D;.;.;.
Sift4G
Uncertain
D;D;D;D
Polyphen
P;.;.;.
Vest4
MutPred
Loss of stability (P = 0.067);.;.;.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at