MUSK

muscle associated receptor tyrosine kinase, the group of I-set domain containing|Immunoglobulin like domain containing|Receptor tyrosine kinases

Basic information

Region (hg38): 9:110668778-110806558

Links

ENSG00000030304 ∙ NCBI:4593 ∙ OMIM:601296 ∙ HGNC:7525 ∙ Uniprot:O15146 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• congenital myasthenic syndrome 9 (Strong), mode of inheritance: AR
• congenital myasthenic syndrome 9 (Strong), mode of inheritance: AR
• fetal akinesia deformation sequence 1 (Supportive), mode of inheritance: AR
• postsynaptic congenital myasthenic syndrome (Supportive), mode of inheritance: AR
• congenital myasthenic syndrome 9 (Strong), mode of inheritance: AR
• fetal akinesia deformation sequence 1 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Myasthenic syndrome, congenital, 9, associated with acetylcholine receptor deficiency	AR	Musculoskeletal; Neurologic; Pharmacogenomic	Most individuals with Myasthenic syndrome, congenital benefit from AChE inhibitors and/or potassium channel blocker 3,4-diaminopyridine (3,4-DAP), though caution must be used in giving 3,4-DAP to young children and individuals with fast-channel syndromes; Some individuals are treated with quinidine, which has some major side effects and may be detrimental in individuals with AChR deficiency	Musculoskeletal; Neurologic	1783919; 8041349; 9120223; 8819551; 9546329; 12771277; 15496425; 15951177; 20301347; 25537362; 25612909
Allelic with Fetal akinesia deformation sequence 2 (AR) likely represents an extreme phenotype of Myasthenic syndrome, congenital, 9, associated with acetylcholine receptor deficiency

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the MUSK gene.

• Congenital myasthenic syndrome 9;Fetal akinesia deformation sequence 1 (219 variants)
• Fetal akinesia deformation sequence 1;Congenital myasthenic syndrome 9 (212 variants)
• not provided (168 variants)
• Congenital myasthenic syndrome 9 (82 variants)
• Inborn genetic diseases (37 variants)
• not specified (36 variants)
• Fetal akinesia deformation sequence 1 (15 variants)
• MUSK-related condition (2 variants)
• Congenital myasthenic syndrome 4C (2 variants)
• Congenital Myasthenic Syndrome, Recessive (2 variants)
• Bilateral ptosis;Stridor;Respiratory insufficiency;Delayed gross motor development (1 variants)
• MUSK-Related Disorders (1 variants)
• Respiratory insufficiency;Delayed gross motor development;Stridor;Bilateral ptosis (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MUSK gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			8	90	5	103
missense		3	244	10	7	264
nonsense	6	4				10
start loss						0
frameshift	4	1				5
inframe indel			5			5
splice donor/acceptor (+/-2bp)	1	5	1			7
splice region			9	15	1	25
non coding			2	51	48	101
Total	11	13	260	151	60

Highest pathogenic variant AF is 0.0000329

Variants in MUSK

This is a list of pathogenic ClinVar variants found in the MUSK region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
9-110668823-T-C		Congenital myasthenic syndrome 9	Benign (Nov 05, 2018)
9-110668862-G-A		Congenital myasthenic syndrome 9	Uncertain significance (Jan 13, 2018)
9-110668906-T-C		Congenital myasthenic syndrome 9;Fetal akinesia deformation sequence 1	Pathogenic (Dec 22, 2023)
9-110668911-G-A		Inborn genetic diseases • Congenital myasthenic syndrome 9;Fetal akinesia deformation sequence 1	Uncertain significance (Nov 09, 2022)
9-110668916-C-A		Fetal akinesia deformation sequence 1;Congenital myasthenic syndrome 9	Likely benign (Sep 06, 2023)
9-110668916-C-G		Congenital myasthenic syndrome 9;Fetal akinesia deformation sequence 1	Likely benign (Jan 04, 2024)
9-110668916-C-T		Fetal akinesia deformation sequence 1;Congenital myasthenic syndrome 9 • MUSK-related disorder	Likely benign (Dec 11, 2023)
9-110668917-G-A		Fetal akinesia deformation sequence 1;Congenital myasthenic syndrome 9	Uncertain significance (May 12, 2022)
9-110668921-A-G		Fetal akinesia deformation sequence 1;Congenital myasthenic syndrome 9	Uncertain significance (Sep 01, 2021)
9-110668924-T-C			Uncertain significance (Nov 27, 2019)
9-110668932-GTACA-G		Congenital myasthenic syndrome 9;Fetal akinesia deformation sequence 1	Pathogenic (Jul 27, 2022)
9-110668934-A-G		Congenital myasthenic syndrome 9;Fetal akinesia deformation sequence 1	Likely benign (Jan 13, 2024)
9-110668937-T-C		Congenital myasthenic syndrome 9;Fetal akinesia deformation sequence 1	Likely benign (Aug 29, 2023)
9-110668943-T-TA		Fetal akinesia deformation sequence 1	Pathogenic (Mar 01, 2015)
9-110668947-C-A		Fetal akinesia deformation sequence 1;Congenital myasthenic syndrome 9	Uncertain significance (Aug 31, 2021)
9-110668961-C-T		Fetal akinesia deformation sequence 1;Congenital myasthenic syndrome 9	Likely benign (Jan 28, 2024)
9-110668962-G-A		Fetal akinesia deformation sequence 1;Congenital myasthenic syndrome 9	Uncertain significance (Sep 17, 2021)
9-110668967-T-C		Fetal akinesia deformation sequence 1;Congenital myasthenic syndrome 9	Likely benign (Aug 22, 2022)
9-110668985-T-G		Congenital myasthenic syndrome 4C • Fetal akinesia deformation sequence 1;Congenital myasthenic syndrome 9 • Congenital myasthenic syndrome 9	Pathogenic (Nov 13, 2023)
9-110668990-T-C		Congenital myasthenic syndrome 9;Fetal akinesia deformation sequence 1	Likely benign (Feb 25, 2023)
9-110668994-G-A		Fetal akinesia deformation sequence 1 • Congenital myasthenic syndrome 9;Fetal akinesia deformation sequence 1	Conflicting classifications of pathogenicity (Jan 28, 2024)
9-110668997-A-G		Congenital myasthenic syndrome 9;Fetal akinesia deformation sequence 1	Likely benign (Sep 30, 2023)
9-110668998-T-C		Fetal akinesia deformation sequence 1;Congenital myasthenic syndrome 9	Likely benign (Apr 21, 2022)
9-110668999-C-T		Congenital myasthenic syndrome 9;Fetal akinesia deformation sequence 1	Likely benign (Apr 25, 2023)
9-110669000-G-A		Fetal akinesia deformation sequence 1;Congenital myasthenic syndrome 9	Likely benign (May 17, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MUSK	protein_coding	protein_coding	ENST00000374448	15	132809

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
4.25e-8	1.00	124609	0	56	124665	0.000225

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.09	409	476	0.859	0.0000251	5668
Missense in Polyphen		191	214.89	0.88881		2545
Synonymous	0.710	170	182	0.933	0.0000103	1724
Loss of Function	3.07	19	39.9	0.476	0.00000218	477

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000380	0.000380
Ashkenazi Jewish	0.00	0.00
East Asian	0.000334	0.000334
Finnish	0.00	0.00
European (Non-Finnish)	0.000293	0.000292
Middle Eastern	0.000334	0.000334
South Asian	0.000295	0.000294
Other	0.000165	0.000165

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Receptor tyrosine kinase which plays a central role in the formation and the maintenance of the neuromuscular junction (NMJ), the synapse between the motor neuron and the skeletal muscle (PubMed:25537362). Recruitment of AGRIN by LRP4 to the MUSK signaling complex induces phosphorylation and activation of MUSK, the kinase of the complex. The activation of MUSK in myotubes regulates the formation of NMJs through the regulation of different processes including the specific expression of genes in subsynaptic nuclei, the reorganization of the actin cytoskeleton and the clustering of the acetylcholine receptors (AChR) in the postsynaptic membrane. May regulate AChR phosphorylation and clustering through activation of ABL1 and Src family kinases which in turn regulate MUSK. DVL1 and PAK1 that form a ternary complex with MUSK are also important for MUSK-dependent regulation of AChR clustering. May positively regulate Rho family GTPases through FNTA. Mediates the phosphorylation of FNTA which promotes prenylation, recruitment to membranes and activation of RAC1 a regulator of the actin cytoskeleton and of gene expression. Other effectors of the MUSK signaling include DNAJA3 which functions downstream of MUSK. May also play a role within the central nervous system by mediating cholinergic responses, synaptic plasticity and memory formation (By similarity). {ECO:0000250, ECO:0000269|PubMed:25537362}.
• Disease: DISEASE: Myasthenic syndrome, congenital, 9, associated with acetylcholine receptor deficiency (CMS9) [MIM:616325]: A form of congenital myasthenic syndrome, a group of disorders characterized by failure of neuromuscular transmission, including pre-synaptic, synaptic, and post-synaptic disorders that are not of autoimmune origin. Clinical features are easy fatigability and muscle weakness affecting the axial and limb muscles (with hypotonia in early-onset forms), the ocular muscles (leading to ptosis and ophthalmoplegia), and the facial and bulbar musculature (affecting sucking and swallowing, and leading to dysphonia). The symptoms fluctuate and worsen with physical effort. CMS9 is a disorder of postsynaptic neuromuscular transmission, due to deficiency of AChR at the endplate that results in low amplitude of the miniature endplate potential and current. {ECO:0000269|PubMed:15496425, ECO:0000269|PubMed:19949040, ECO:0000269|PubMed:20371544, ECO:0000269|PubMed:23326516, ECO:0000269|PubMed:24183479}. Note=The disease is caused by mutations affecting the gene represented in this entry. MUSK mutations lead to decreased agrin- dependent AChR aggregation, a critical step in the formation of the neuromuscular junction.; DISEASE: Fetal akinesia deformation sequence (FADS) [MIM:208150]: A clinically and genetically heterogeneous group of disorders with congenital malformations related to impaired fetal movement. Clinical features include fetal akinesia, intrauterine growth retardation, polyhydramnios, arthrogryposis, pulmonary hypoplasia, craniofacial abnormalities, and cryptorchidism. {ECO:0000269|PubMed:25537362, ECO:0000269|PubMed:25612909}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Extracellular matrix organization;role of nicotinic acetylcholine receptors in the regulation of apoptosis;agrin in postsynaptic differentiation;ECM proteoglycans (Consensus)

Recessive Scores

• pRec: 0.779

Intolerance Scores

• loftool: 0.392
• rvis_EVS: 0.52
• rvis_percentile_EVS: 80.34

Haploinsufficiency Scores

• pHI: 0.442
• hipred: N
• hipred_score: 0.492
• ghis: 0.396

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.671

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Musk
• Phenotype: integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; cellular phenotype; homeostasis/metabolism phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); muscle phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype; skeleton phenotype

Zebrafish Information Network

• Gene name: musk
• Affected structure: primary motor neuron
• Phenotype tag: abnormal
• Phenotype quality: morphology

Gene ontology

• Biological process: positive regulation of protein phosphorylation;transmembrane receptor protein tyrosine kinase signaling pathway;multicellular organism development;neuromuscular junction development;memory;regulation of synaptic growth at neuromuscular junction;positive regulation of gene expression;peptidyl-tyrosine phosphorylation;protein autophosphorylation;anatomical structure development;skeletal muscle acetylcholine-gated channel clustering;positive regulation of protein geranylgeranylation
• Cellular component: integral component of plasma membrane;cell junction;neuromuscular junction;receptor complex;postsynaptic membrane
• Molecular function: protein tyrosine kinase activity;transmembrane receptor protein tyrosine kinase activity;protein binding;ATP binding;Wnt-protein binding;metal ion binding