rs55980069

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005592.4(MUSK):c.398T>C(p.Ile133Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00592 in 1,539,768 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I133V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0061 ( 38 hom. )

Consequence

MUSK
NM_005592.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.74

Publications

5 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=0.006833166).

BP6

Variant 9-110695442-T-C is Benign according to our data. Variant chr9-110695442-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 197256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00393 (599/152300) while in subpopulation NFE AF = 0.0061 (415/68006). AF 95% confidence interval is 0.00562. There are 0 homozygotes in GnomAd4. There are 298 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 38 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUSK	NM_005592.4 link	c.398T>C	p.Ile133Thr	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.398T>C	p.Ile133Thr	missense_variant	Exon 4 of 15	5	NM_005592.4	ENSP00000363571.4	O15146-1
MUSK	ENST00000416899.7 link	c.398T>C	p.Ile133Thr	missense_variant	Exon 4 of 14	5		ENSP00000393608.3	A0A087WSY1
MUSK	ENST00000189978.10 link	c.398T>C	p.Ile133Thr	missense_variant	Exon 4 of 14	5		ENSP00000189978.6	O15146-2
MUSK	ENST00000374439.1 link	c.92T>C	p.Ile31Thr	missense_variant	Exon 2 of 4	5		ENSP00000363562.2	F6XAJ2

Frequencies

GnomAD3 genomes

AF:

0.00394

AC:

599

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00111

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00268

Gnomad ASJ

AF:

0.0112

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00245

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00610

Gnomad OTH

AF:

0.00764

GnomAD2 exomes

AF:

0.00451

AC:

796

AN:

176308

AF XY:

0.00443

show subpopulations

Gnomad AFR exome

AF:

0.00132

Gnomad AMR exome

AF:

0.00260

Gnomad ASJ exome

AF:

0.0109

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00209

Gnomad NFE exome

AF:

0.00673

Gnomad OTH exome

AF:

0.00553

GnomAD4 exome

AF:

0.00613

AC:

8511

AN:

1387468

Hom.:

Cov.:

AF XY:

0.00600

AC XY:

4122

AN XY:

686668

show subpopulations

African (AFR)

AF:

0.00104

AC:

AN:

31828

American (AMR)

AF:

0.00321

AC:

119

AN:

37026

Ashkenazi Jewish (ASJ)

AF:

0.0110

AC:

276

AN:

25128

East Asian (EAS)

AF:

0.0000267

AC:

AN:

37424

South Asian (SAS)

AF:

0.00299

AC:

232

AN:

77716

European-Finnish (FIN)

AF:

0.00207

AC:

105

AN:

50622

Middle Eastern (MID)

AF:

0.00388

AC:

AN:

5666

European-Non Finnish (NFE)

AF:

0.00694

AC:

7389

AN:

1064228

Other (OTH)

AF:

0.00578

AC:

334

AN:

57830

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

397

793

1190

1586

1983

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

298

596

894

1192

1490

<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:

0.00393

AC:

599

AN:

152300

Hom.:

Cov.:

AF XY:

0.00400

AC XY:

298

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00111

AC:

AN:

41578

American (AMR)

AF:

0.00268

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0112

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00269

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00245

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00610

AC:

415

AN:

68006

Other (OTH)

AF:

0.00756

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

120

150

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00559

Hom.:

Bravo

AF:

0.00403

TwinsUK

AF:

0.00728

AC:

ALSPAC

AF:

0.00545

AC:

ESP6500AA

AF:

0.00110

AC:

ESP6500EA

AF:

0.00690

AC:

ExAC

AF:

0.00323

AC:

384

Asia WGS

AF:

0.00115

AC:

AN:

3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Mar 05, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 13, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MUSK: BS2 -

not specified

Benign:2

Dec 17, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 04, 2017

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. -

MUSK-related disorder

Benign:1

Jun 29, 2020

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.13

T;.;.;.;.

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.40

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.86

D;D;D;D;D

MetaRNN

Benign

0.0068

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.53

N;.;N;.;.

PhyloP100

2.7

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.0

N;N;N;.;.

REVEL

Benign

0.042

Sift

Benign

0.061

T;T;T;.;.

Sift4G

Benign

0.62

T;T;T;T;T

Polyphen

0.0060

B;.;.;.;.

Vest4

0.35

MVP

0.36

MPC

0.21

ClinPred

0.019

GERP RS

1.2

Varity_R

0.071

gMVP

0.67

Mutation Taster

=93/7

polymorphism

(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