NM_005592.4:c.537C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_005592.4(MUSK):c.537C>T(p.Asn179Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.173 in 1,610,998 control chromosomes in the GnomAD database, including 25,666 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 1786 hom., cov: 31)

Exomes 𝑓: 0.18 ( 23880 hom. )

Consequence

MUSK
NM_005592.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0990

Publications

13 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.32).

BP6

Variant 9-110697375-C-T is Benign according to our data. Variant chr9-110697375-C-T is described in ClinVar as Benign. ClinVar VariationId is 129637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.099 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUSK	NM_005592.4 link	c.537C>T	p.Asn179Asn	synonymous_variant	Exon 5 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.537C>T	p.Asn179Asn	synonymous_variant	Exon 5 of 15	5	NM_005592.4	ENSP00000363571.4	O15146-1
MUSK	ENST00000416899.7 link	c.537C>T	p.Asn179Asn	synonymous_variant	Exon 5 of 14	5		ENSP00000393608.3	A0A087WSY1
MUSK	ENST00000189978.10 link	c.537C>T	p.Asn179Asn	synonymous_variant	Exon 5 of 14	5		ENSP00000189978.6	O15146-2
MUSK	ENST00000374439.1 link	c.231C>T	p.Asn77Asn	synonymous_variant	Exon 3 of 4	5		ENSP00000363562.2	F6XAJ2

Frequencies

GnomAD3 genomes

AF:

0.135

AC:

20532

AN:

151848

Hom.:

1780

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0302

Gnomad AMI

AF:

0.196

Gnomad AMR

AF:

0.0894

Gnomad ASJ

AF:

0.187

Gnomad EAS

AF:

0.197

Gnomad SAS

AF:

0.174

Gnomad FIN

AF:

0.257

Gnomad MID

AF:

0.108

Gnomad NFE

AF:

0.181

Gnomad OTH

AF:

0.109

GnomAD2 exomes

AF:

0.161

AC:

39982

AN:

248244

AF XY:

0.167

show subpopulations

Gnomad AFR exome

AF:

0.0262

Gnomad AMR exome

AF:

0.0661

Gnomad ASJ exome

AF:

0.186

Gnomad EAS exome

AF:

0.194

Gnomad FIN exome

AF:

0.253

Gnomad NFE exome

AF:

0.177

Gnomad OTH exome

AF:

0.164

GnomAD4 exome

AF:

0.177

AC:

258273

AN:

1459032

Hom.:

23880

Cov.:

AF XY:

0.178

AC XY:

129126

AN XY:

725780

show subpopulations

African (AFR)

AF:

0.0259

AC:

867

AN:

33448

American (AMR)

AF:

0.0695

AC:

3098

AN:

44602

Ashkenazi Jewish (ASJ)

AF:

0.185

AC:

4821

AN:

26070

East Asian (EAS)

AF:

0.184

AC:

7292

AN:

39600

South Asian (SAS)

AF:

0.180

AC:

15449

AN:

85712

European-Finnish (FIN)

AF:

0.246

AC:

13130

AN:

53290

Middle Eastern (MID)

AF:

0.141

AC:

813

AN:

5764

European-Non Finnish (NFE)

AF:

0.183

AC:

202898

AN:

1110272

Other (OTH)

AF:

0.164

AC:

9905

AN:

60274

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

10193

20386

30578

40771

50964

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7122

14244

21366

28488

35610

<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:

0.135

AC:

20542

AN:

151966

Hom.:

1786

Cov.:

AF XY:

0.139

AC XY:

10297

AN XY:

74274

show subpopulations

African (AFR)

AF:

0.0301

AC:

1247

AN:

41480

American (AMR)

AF:

0.0891

AC:

1361

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.187

AC:

650

AN:

3468

East Asian (EAS)

AF:

0.197

AC:

1018

AN:

5162

South Asian (SAS)

AF:

0.175

AC:

841

AN:

4814

European-Finnish (FIN)

AF:

0.257

AC:

2704

AN:

10510

Middle Eastern (MID)

AF:

0.105

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.181

AC:

12273

AN:

67952

Other (OTH)

AF:

0.113

AC:

239

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

876

1751

2627

3502

4378

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

238

476

714

952

1190

<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:

0.154

Hom.:

1678

Bravo

AF:

0.117

Asia WGS

AF:

0.163

AC:

568

AN:

3478

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. -

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

-0.32

CADD

Benign

(source)

DANN

Benign

0.66

PhyloP100

0.099

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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