chr9-110687127-A-AC

Variant names:

• chr9-110687127-A-AC
• rs879255561
• NM_005592.4:c.220dupC

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_005592.4(MUSK):​c.220dupC​(p.Arg74ProfsTer20) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. R74R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MUSK NM_005592.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.36
• Publications: 1 publications found

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]

MUSK Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 9

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
• fetal akinesia deformation sequence 1

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-110687127-A-AC is Pathogenic according to our data. Variant chr9-110687127-A-AC is described in CliVar as Pathogenic. Clinvar id is 8240.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr9-110687127-A-AC is described in CliVar as Pathogenic. Clinvar id is 8240.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr9-110687127-A-AC is described in CliVar as Pathogenic. Clinvar id is 8240.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr9-110687127-A-AC is described in CliVar as Pathogenic. Clinvar id is 8240.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr9-110687127-A-AC is described in CliVar as Pathogenic. Clinvar id is 8240.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr9-110687127-A-AC is described in CliVar as Pathogenic. Clinvar id is 8240.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUSK	NM_005592.4	c.220dupC	p.Arg74ProfsTer20	frameshift_variant	Exon 3 of 15	ENST00000374448.9	NP_005583.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUSK	ENST00000374448.9	c.220dupC	p.Arg74ProfsTer20	frameshift_variant	Exon 3 of 15	5	NM_005592.4	ENSP00000363571.4
MUSK	ENST00000416899.7	c.220dupC	p.Arg74ProfsTer20	frameshift_variant	Exon 3 of 14	5		ENSP00000393608.3
MUSK	ENST00000189978.10	c.220dupC	p.Arg74ProfsTer20	frameshift_variant	Exon 3 of 14	5		ENSP00000189978.6
MUSK	ENST00000374439.1	c.-90_-89insC		upstream_gene_variant		5		ENSP00000363562.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Congenital myasthenic syndrome 9 Pathogenic:1

Dec 15, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.4
Mutation Taster		=3/197	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs879255561; hg19: chr9-113449407;