rs2274419

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.1239G>A(p.Met413Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 1,613,518 control chromosomes in the GnomAD database, including 14,411 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M413T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.099 ( 963 hom., cov: 32)

Exomes 𝑓: 0.13 ( 13448 hom. )

Consequence

MUSK
NM_005592.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.872

Publications

25 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:

LOC107987115 (HGNC:):

LOC107987115 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=0.0040370524).

BP6

Variant 9-110775842-G-A is Benign according to our data. Variant chr9-110775842-G-A is described in ClinVar as Benign. ClinVar VariationId is 129630.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.191 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUSK	NM_005592.4 link	c.1239G>A	p.Met413Ile	missense_variant	Exon 10 of 15	ENST00000374448.9	NP_005583.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MUSK	ENST00000374448.9 link	c.1239G>A	p.Met413Ile	missense_variant	Exon 10 of 15	5	NM_005592.4	ENSP00000363571.4
MUSK	ENST00000416899.7 link	c.1239G>A	p.Met413Ile	missense_variant	Exon 10 of 14	5		ENSP00000393608.3
MUSK	ENST00000189978.10 link	c.1005G>A	p.Met335Ile	missense_variant	Exon 10 of 14	5		ENSP00000189978.6
MUSK	ENST00000374438.1 link	n.496G>A		non_coding_transcript_exon_variant	Exon 1 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.0988

AC:

15021

AN:

151960

Hom.:

964

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0223

Gnomad AMI

AF:

0.163

Gnomad AMR

AF:

0.0551

Gnomad ASJ

AF:

0.103

Gnomad EAS

AF:

0.201

Gnomad SAS

AF:

0.147

Gnomad FIN

AF:

0.156

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.135

Gnomad OTH

AF:

0.0705

GnomAD2 exomes

AF:

0.120

AC:

29807

AN:

249200

AF XY:

0.124

show subpopulations

Gnomad AFR exome

AF:

0.0197

Gnomad AMR exome

AF:

0.0403

Gnomad ASJ exome

AF:

0.0978

Gnomad EAS exome

AF:

0.196

Gnomad FIN exome

AF:

0.158

Gnomad NFE exome

AF:

0.133

Gnomad OTH exome

AF:

0.107

GnomAD4 exome

AF:

0.132

AC:

192302

AN:

1461440

Hom.:

13448

Cov.:

AF XY:

0.133

AC XY:

96646

AN XY:

727022

show subpopulations

African (AFR)

AF:

0.0172

AC:

577

AN:

33476

American (AMR)

AF:

0.0413

AC:

1846

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.100

AC:

2622

AN:

26132

East Asian (EAS)

AF:

0.224

AC:

8878

AN:

39694

South Asian (SAS)

AF:

0.148

AC:

12732

AN:

86256

European-Finnish (FIN)

AF:

0.158

AC:

8439

AN:

53398

Middle Eastern (MID)

AF:

0.0570

AC:

329

AN:

5768

European-Non Finnish (NFE)

AF:

0.135

AC:

150152

AN:

1111628

Other (OTH)

AF:

0.111

AC:

6727

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

8520

17040

25560

34080

42600

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5368

10736

16104

21472

26840

<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:

0.0988

AC:

15020

AN:

152078

Hom.:

963

Cov.:

AF XY:

0.100

AC XY:

7443

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.0223

AC:

925

AN:

41516

American (AMR)

AF:

0.0550

AC:

841

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.103

AC:

356

AN:

3468

East Asian (EAS)

AF:

0.201

AC:

1039

AN:

5160

South Asian (SAS)

AF:

0.148

AC:

710

AN:

4810

European-Finnish (FIN)

AF:

0.156

AC:

1650

AN:

10564

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.135

AC:

9191

AN:

67962

Other (OTH)

AF:

0.0707

AC:

149

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

681

1363

2044

2726

3407

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

186

372

558

744

930

<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:

0.116

Hom.:

2562

Bravo

AF:

0.0861

TwinsUK

AF:

0.135

AC:

501

ALSPAC

AF:

0.137

AC:

527

ESP6500AA

AF:

0.0219

AC:

ESP6500EA

AF:

0.133

AC:

1094

ExAC

AF:

0.121

AC:

14602

Asia WGS

AF:

0.162

AC:

562

AN:

3478

EpiCase

AF:

0.127

EpiControl

AF:

0.120

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

May 20, 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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

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 13, 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

Pathogenic

0.62

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.075

T;.;.;.

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.47

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.85

T;T;D;D

MetaRNN

Benign

0.0040

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.88

L;.;.;.

PhyloP100

0.87

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.18

N;.;.;.

REVEL

Benign

0.063

Sift

Benign

0.60

T;.;.;.

Sift4G

Benign

0.50

T;T;T;T

Polyphen

0.0

B;.;.;.

Vest4

0.048

MutPred

0.48

Gain of methylation at K416 (P = 0.0832);Gain of methylation at K416 (P = 0.0832);.;.;

MPC

0.18

ClinPred

0.0050

GERP RS

1.1

Varity_R

0.052

gMVP

0.23

Mutation Taster

=81/19

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

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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