rs199476083

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_005592.4(MUSK):c.2368G>A(p.Val790Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000126 in 1,613,878 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

MUSK
NM_005592.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6U:2

Conservation

PhyloP100: 10.0

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 9-110800746-G-A is Pathogenic according to our data. Variant chr9-110800746-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-110800746-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUSK	NM_005592.4 linkuse as main transcript	c.2368G>A	p.Val790Met	missense_variant	15/15	ENST00000374448.9	NP_005583.1	O15146-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MUSK	ENST00000374448.9 linkuse as main transcript	c.2368G>A	p.Val790Met	missense_variant	15/15	5	NM_005592.4	ENSP00000363571.4	O15146-1
MUSK	ENST00000416899.7 linkuse as main transcript	c.2344G>A	p.Val782Met	missense_variant	14/14	5		ENSP00000393608.3	A0A087WSY1
MUSK	ENST00000189978.10 linkuse as main transcript	c.2110G>A	p.Val704Met	missense_variant	14/14	5		ENSP00000189978.6	O15146-2

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000229

AC:

AN:

249208

Hom.:

AF XY:

0.000207

AC XY:

AN XY:

135196

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.000435

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.000292

Gnomad OTH exome

AF:

0.000992

GnomAD4 exome

AF:

0.000122

AC:

178

AN:

1461712

Hom.:

Cov.:

AF XY:

0.000127

AC XY:

AN XY:

727138

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.000514

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000113

Gnomad4 OTH exome

AF:

0.000282

GnomAD4 genome

AF:

0.000164

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.000589

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000223

Hom.:

Bravo

AF:

0.000329

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000357

AC:

ExAC

AF:

0.000265

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000237

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27588369, 24122059, 31892318, 20371544, 16794080, 25562515, 30429133, 34426522, 15496425, 25537362) -
Uncertain significance, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Jul 09, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 21, 2020	- -

Congenital myasthenic syndrome 9

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 15, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -

MUSK-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 14, 2023

Variant summary: MUSK c.2368G>A (p.Val790Met) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 249208 control chromosomes. c.2368G>A has been reported in the literature in multiple compound heterozygous individuals affected with congenital myasthenis syndrome (e.g. Chevessier_2004, Maggi_2015, Younas_2018). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effects were reduced protein levels and stability in vitro, altered agrin-dependent acetylcholine receptor aggregation in vitro, and disassociation of nerve terminals with acetylcholine aggregates in vivo (e.g. Chevessier_2004, BenAmmar_2013). The following publications have been ascertained in the context of this evaluation (PMID: 23326516, 15496425, 24122059, 30429133). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as pathogenic (n=2), likely pathogenic (n=1), or uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 06, 2024

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 790 of the MUSK protein (p.Val790Met). This variant is present in population databases (rs199476083, gnomAD 0.04%). This missense change has been observed in individuals with congenital myasthenic syndrome (CMS) (PMID: 15496425, 24122059, 30429133). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8239). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects MUSK function (PMID: 15496425, 23326516). For these reasons, this variant has been classified as Pathogenic. -

Fetal akinesia deformation sequence 1

Uncertain:1

Uncertain significance, flagged submission

clinical testing

Baylor Genetics

Feb 07, 2020

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Uncertain

0.088

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.60

D;.;.;.

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D;D

M_CAP

Benign

0.055

MetaRNN

Uncertain

0.70

D;D;D;D

MetaSVM

Uncertain

-0.22

MutationAssessor

Uncertain

2.1

M;.;.;.

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-2.9

D;.;.;.

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0010

D;.;.;.

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.94

MVP

0.68

MPC

0.69

ClinPred

0.23

GERP RS

5.3

Varity_R

0.81

gMVP

0.88

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over