9-110695519-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005592.4(MUSK):c.475A>G(p.Ser159Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 1,555,198 control chromosomes in the GnomAD database, including 20,579 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1533 hom., cov: 32)

Exomes 𝑓: 0.16 ( 19046 hom. )

Consequence

MUSK
NM_005592.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.62

Publications

23 publications found

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 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

MUSK links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0034041703).

BP6

Variant 9-110695519-A-G is Benign according to our data. Variant chr9-110695519-A-G is described in ClinVar as Benign. ClinVar VariationId is 129636.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.19 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUSK	NM_005592.4 link	c.475A>G	p.Ser159Gly	missense_variant	Exon 4 of 15	ENST00000374448.9	NP_005583.1	O15146-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MUSK	ENST00000374448.9 link	c.475A>G	p.Ser159Gly	missense_variant	Exon 4 of 15	5	NM_005592.4	ENSP00000363571.4	O15146-1
MUSK	ENST00000416899.7 link	c.475A>G	p.Ser159Gly	missense_variant	Exon 4 of 14	5		ENSP00000393608.3	A0A087WSY1
MUSK	ENST00000189978.10 link	c.475A>G	p.Ser159Gly	missense_variant	Exon 4 of 14	5		ENSP00000189978.6	O15146-2
MUSK	ENST00000374439.1 link	c.169A>G	p.Ser57Gly	missense_variant	Exon 2 of 4	5		ENSP00000363562.2	F6XAJ2

Frequencies

GnomAD3 genomes

AF:

0.124

AC:

18932

AN:

152156

Hom.:

1528

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0276

Gnomad AMI

AF:

0.164

Gnomad AMR

AF:

0.0804

Gnomad ASJ

AF:

0.164

Gnomad EAS

AF:

0.200

Gnomad SAS

AF:

0.149

Gnomad FIN

AF:

0.250

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.165

Gnomad OTH

AF:

0.0981

GnomAD2 exomes

AF:

0.148

AC:

26461

AN:

178208

AF XY:

0.152

show subpopulations

Gnomad AFR exome

AF:

0.0239

Gnomad AMR exome

AF:

0.0613

Gnomad ASJ exome

AF:

0.169

Gnomad EAS exome

AF:

0.199

Gnomad FIN exome

AF:

0.244

Gnomad NFE exome

AF:

0.161

Gnomad OTH exome

AF:

0.148

GnomAD4 exome

AF:

0.161

AC:

225809

AN:

1402922

Hom.:

19046

Cov.:

AF XY:

0.161

AC XY:

111801

AN XY:

693436

show subpopulations

African (AFR)

AF:

0.0231

AC:

741

AN:

32070

American (AMR)

AF:

0.0629

AC:

2351

AN:

37394

Ashkenazi Jewish (ASJ)

AF:

0.165

AC:

4173

AN:

25224

East Asian (EAS)

AF:

0.186

AC:

6905

AN:

37170

South Asian (SAS)

AF:

0.148

AC:

11615

AN:

78548

European-Finnish (FIN)

AF:

0.237

AC:

12021

AN:

50692

Middle Eastern (MID)

AF:

0.129

AC:

736

AN:

5696

European-Non Finnish (NFE)

AF:

0.166

AC:

178492

AN:

1077762

Other (OTH)

AF:

0.150

AC:

8775

AN:

58366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

Heterozygous variant carriers

8392

16785

25177

33570

41962

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6374

12748

19122

25496

31870

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.124

AC:

18941

AN:

152276

Hom.:

1533

Cov.:

AF XY:

0.128

AC XY:

9534

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.0275

AC:

1144

AN:

41584

American (AMR)

AF:

0.0802

AC:

1227

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.164

AC:

570

AN:

3468

East Asian (EAS)

AF:

0.200

AC:

1038

AN:

5188

South Asian (SAS)

AF:

0.150

AC:

724

AN:

4834

European-Finnish (FIN)

AF:

0.250

AC:

2649

AN:

10594

Middle Eastern (MID)

AF:

0.0918

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.165

AC:

11196

AN:

67990

Other (OTH)

AF:

0.102

AC:

216

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

823

1647

2470

3294

4117

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

220

440

660

880

1100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.134

Hom.:

1578

Bravo

AF:

0.107

TwinsUK

AF:

0.177

AC:

657

ALSPAC

AF:

0.172

AC:

662

ESP6500AA

AF:

0.0330

AC:

120

ESP6500EA

AF:

0.154

AC:

1249

ExAC

AF:

0.119

AC:

13958

Asia WGS

AF:

0.155

AC:

539

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Feb 19, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Congenital myasthenic syndrome 9

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.095

T;.;.;.;.

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.081

LIST_S2

Benign

0.80

T;T;T;T;T

MetaRNN

Benign

0.0034

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.34

N;.;N;.;.

PhyloP100

1.6

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.78

N;N;N;.;.

REVEL

Benign

0.061

Sift

Benign

0.32

T;T;T;.;.

Sift4G

Benign

0.38

T;T;T;T;T

Polyphen

0.0020

B;.;.;.;.

Vest4

0.045

MPC

0.15

ClinPred

0.0031

GERP RS

3.4

Varity_R

0.17

gMVP

0.31

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over