rs10980531

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_005592.4(MUSK):c.402G>A(p.Glu134Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.175 in 1,535,178 control chromosomes in the GnomAD database, including 24,102 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 2166 hom., cov: 33)

Exomes 𝑓: 0.18 ( 21936 hom. )

Consequence

MUSK
NM_005592.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.227

Publications

9 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 9-110695446-G-A is Benign according to our data. Variant chr9-110695446-G-A is described in ClinVar as Benign. ClinVar VariationId is 129635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.227 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.203 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUSK	NM_005592.4 link	c.402G>A	p.Glu134Glu	synonymous_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.402G>A	p.Glu134Glu	synonymous_variant	Exon 4 of 15	5	NM_005592.4	ENSP00000363571.4	O15146-1
MUSK	ENST00000416899.7 link	c.402G>A	p.Glu134Glu	synonymous_variant	Exon 4 of 14	5		ENSP00000393608.3	A0A087WSY1
MUSK	ENST00000189978.10 link	c.402G>A	p.Glu134Glu	synonymous_variant	Exon 4 of 14	5		ENSP00000189978.6	O15146-2
MUSK	ENST00000374439.1 link	c.96G>A	p.Glu32Glu	synonymous_variant	Exon 2 of 4	5		ENSP00000363562.2	F6XAJ2

Frequencies

GnomAD3 genomes

AF:

0.166

AC:

25184

AN:

151970

Hom.:

2163

Cov.:

show subpopulations

Gnomad AFR

AF:

0.142

Gnomad AMI

AF:

0.0758

Gnomad AMR

AF:

0.140

Gnomad ASJ

AF:

0.141

Gnomad EAS

AF:

0.214

Gnomad SAS

AF:

0.184

Gnomad FIN

AF:

0.145

Gnomad MID

AF:

0.161

Gnomad NFE

AF:

0.187

Gnomad OTH

AF:

0.160

GnomAD2 exomes

AF:

0.159

AC:

27829

AN:

175058

AF XY:

0.163

show subpopulations

Gnomad AFR exome

AF:

0.131

Gnomad AMR exome

AF:

0.0848

Gnomad ASJ exome

AF:

0.132

Gnomad EAS exome

AF:

0.212

Gnomad FIN exome

AF:

0.157

Gnomad NFE exome

AF:

0.178

Gnomad OTH exome

AF:

0.164

GnomAD4 exome

AF:

0.176

AC:

242898

AN:

1383090

Hom.:

21936

Cov.:

AF XY:

0.176

AC XY:

120764

AN XY:

684428

show subpopulations

African (AFR)

AF:

0.135

AC:

4275

AN:

31700

American (AMR)

AF:

0.0927

AC:

3411

AN:

36788

Ashkenazi Jewish (ASJ)

AF:

0.132

AC:

3300

AN:

25062

East Asian (EAS)

AF:

0.226

AC:

8410

AN:

37210

South Asian (SAS)

AF:

0.180

AC:

13913

AN:

77094

European-Finnish (FIN)

AF:

0.160

AC:

8063

AN:

50508

Middle Eastern (MID)

AF:

0.160

AC:

905

AN:

5668

European-Non Finnish (NFE)

AF:

0.180

AC:

190766

AN:

1061362

Other (OTH)

AF:

0.171

AC:

9855

AN:

57698

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

8422

16844

25267

33689

42111

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6634

13268

19902

26536

33170

<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:

0.166

AC:

25199

AN:

152088

Hom.:

2166

Cov.:

AF XY:

0.164

AC XY:

12180

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.142

AC:

5890

AN:

41482

American (AMR)

AF:

0.139

AC:

2128

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.141

AC:

489

AN:

3468

East Asian (EAS)

AF:

0.214

AC:

1106

AN:

5172

South Asian (SAS)

AF:

0.183

AC:

883

AN:

4820

European-Finnish (FIN)

AF:

0.145

AC:

1536

AN:

10572

Middle Eastern (MID)

AF:

0.163

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.187

AC:

12709

AN:

67982

Other (OTH)

AF:

0.161

AC:

341

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1109

2217

3326

4434

5543

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

284

568

852

1136

1420

<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:

0.173

Hom.:

1212

Bravo

AF:

0.159

Asia WGS

AF:

0.185

AC:

640

AN:

3472

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

May 27, 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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

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

BayesDel_noAF

Benign

-0.52

CADD

Benign

4.1

(source)

DANN

Benign

0.49

PhyloP100

0.23

Mutation Taster

=92/8

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