rs56044404
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Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2
The NM_005592.4(MUSK):āc.666T>Cā(p.Asn222=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00285 in 1,613,162 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.0020 ( 0 hom., cov: 32)
Exomes š: 0.0029 ( 5 hom. )
Consequence
MUSK
NM_005592.4 synonymous
NM_005592.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.933
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 Benign. Variant got -14 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.5).
BP6
Variant 9-110734288-T-C is Benign according to our data. Variant chr9-110734288-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 259812.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=2}. Variant chr9-110734288-T-C is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=0.933 with no splicing effect.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00196 (298/152216) while in subpopulation NFE AF= 0.00349 (237/67994). AF 95% confidence interval is 0.00312. There are 0 homozygotes in gnomad4. There are 122 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 5 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MUSK | NM_005592.4 | c.666T>C | p.Asn222= | synonymous_variant | 6/15 | ENST00000374448.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MUSK | ENST00000374448.9 | c.666T>C | p.Asn222= | synonymous_variant | 6/15 | 5 | NM_005592.4 | P4 | |
MUSK | ENST00000416899.7 | c.666T>C | p.Asn222= | synonymous_variant | 6/14 | 5 | A1 | ||
MUSK | ENST00000189978.10 | c.696T>C | p.Asn232= | synonymous_variant | 7/14 | 5 | |||
MUSK | ENST00000634612.1 | n.88T>C | non_coding_transcript_exon_variant | 3/6 | 5 |
Frequencies
GnomAD3 genomes AF: 0.00196 AC: 298AN: 152098Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00222 AC: 553AN: 248704Hom.: 2 AF XY: 0.00221 AC XY: 298AN XY: 134928
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GnomAD4 exome AF: 0.00295 AC: 4307AN: 1460946Hom.: 5 Cov.: 31 AF XY: 0.00302 AC XY: 2198AN XY: 726748
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GnomAD4 genome AF: 0.00196 AC: 298AN: 152216Hom.: 0 Cov.: 32 AF XY: 0.00164 AC XY: 122AN XY: 74422
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:5
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 19, 2016 | - - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 10, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2024 | MUSK: BP4, BP7 - |
Congenital myasthenic syndrome 9 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Fetal akinesia deformation sequence 1;C4225368:Congenital myasthenic syndrome 9 Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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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