chr9-110668932-GTACA-G

Variant names:

• chr9-110668932-GTACA-G
• NM_005592.4:c.31_34delCATA

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_005592.4(MUSK):​c.31_34delCATA​(p.His11PhefsTer29) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. H11H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MUSK NM_005592.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.85
• Publications: 0 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 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 62 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-110668932-GTACA-G is Pathogenic according to our data. Variant chr9-110668932-GTACA-G is described in ClinVar as [Pathogenic]. Clinvar id is 2018617.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUSK	NM_005592.4	c.31_34delCATA	p.His11PhefsTer29	frameshift_variant	Exon 1 of 15	ENST00000374448.9	NP_005583.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUSK	ENST00000374448.9	c.31_34delCATA	p.His11PhefsTer29	frameshift_variant	Exon 1 of 15	5	NM_005592.4	ENSP00000363571.4
MUSK	ENST00000416899.7	c.31_34delCATA	p.His11PhefsTer29	frameshift_variant	Exon 1 of 14	5		ENSP00000393608.3
MUSK	ENST00000189978.10	c.31_34delCATA	p.His11PhefsTer29	frameshift_variant	Exon 1 of 14	5		ENSP00000189978.6

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Fetal akinesia deformation sequence 1;C4225368:Congenital myasthenic syndrome 9 Pathogenic:1

Jul 27, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with MUSK-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.His11Phefs*29) in the MUSK gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MUSK are known to be pathogenic (PMID: 8653786, 25612909, 25695962, 25900532). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.9

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

hg19: chr9-113431212;