NM_005592.4:c.299C>T

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.299C>T(p.Thr100Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0269 in 1,613,722 control chromosomes in the GnomAD database, including 711 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T100T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.021 ( 44 hom., cov: 31)

Exomes 𝑓: 0.027 ( 667 hom. )

Consequence

MUSK
NM_005592.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.213

Publications

19 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=0.0064065754).

BP6

Variant 9-110687209-C-T is Benign according to our data. Variant chr9-110687209-C-T is described in ClinVar as Benign. ClinVar VariationId is 129634.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 = 0.0213 (3236/152218) while in subpopulation NFE AF = 0.0324 (2206/68016). AF 95% confidence interval is 0.0313. There are 44 homozygotes in GnomAd4. There are 1504 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 44 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUSK	NM_005592.4 link	c.299C>T	p.Thr100Met	missense_variant	Exon 3 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.299C>T	p.Thr100Met	missense_variant	Exon 3 of 15	5	NM_005592.4	ENSP00000363571.4	O15146-1
MUSK	ENST00000416899.7 link	c.299C>T	p.Thr100Met	missense_variant	Exon 3 of 14	5		ENSP00000393608.3	A0A087WSY1
MUSK	ENST00000189978.10 link	c.299C>T	p.Thr100Met	missense_variant	Exon 3 of 14	5		ENSP00000189978.6	O15146-2
MUSK	ENST00000374439.1 link	c.-8C>T		upstream_gene_variant		5		ENSP00000363562.2	F6XAJ2

Frequencies

GnomAD3 genomes

AF:

0.0213

AC:

3236

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00625

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.0191

Gnomad ASJ

AF:

0.0259

Gnomad EAS

AF:

0.00174

Gnomad SAS

AF:

0.00311

Gnomad FIN

AF:

0.0290

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0324

Gnomad OTH

AF:

0.0196

GnomAD2 exomes

AF:

0.0230

AC:

5741

AN:

249182

AF XY:

0.0230

show subpopulations

Gnomad AFR exome

AF:

0.00568

Gnomad AMR exome

AF:

0.0123

Gnomad ASJ exome

AF:

0.0276

Gnomad EAS exome

AF:

0.00362

Gnomad FIN exome

AF:

0.0310

Gnomad NFE exome

AF:

0.0348

Gnomad OTH exome

AF:

0.0246

GnomAD4 exome

AF:

0.0274

AC:

40103

AN:

1461504

Hom.:

667

Cov.:

AF XY:

0.0269

AC XY:

19524

AN XY:

727020

show subpopulations

African (AFR)

AF:

0.00463

AC:

155

AN:

33474

American (AMR)

AF:

0.0125

AC:

561

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0253

AC:

661

AN:

26134

East Asian (EAS)

AF:

0.00146

AC:

AN:

39698

South Asian (SAS)

AF:

0.00450

AC:

388

AN:

86250

European-Finnish (FIN)

AF:

0.0309

AC:

1648

AN:

53386

Middle Eastern (MID)

AF:

0.0179

AC:

103

AN:

5764

European-Non Finnish (NFE)

AF:

0.0315

AC:

35010

AN:

1111714

Other (OTH)

AF:

0.0252

AC:

1519

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

2037

4074

6111

8148

10185

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1238

2476

3714

4952

6190

<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:

0.0213

AC:

3236

AN:

152218

Hom.:

Cov.:

AF XY:

0.0202

AC XY:

1504

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.00623

AC:

259

AN:

41546

American (AMR)

AF:

0.0190

AC:

291

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0259

AC:

AN:

3472

East Asian (EAS)

AF:

0.00174

AC:

AN:

5170

South Asian (SAS)

AF:

0.00311

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0290

AC:

307

AN:

10592

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0324

AC:

2206

AN:

68016

Other (OTH)

AF:

0.0199

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

163

327

490

654

817

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.0284

Hom.:

245

Bravo

AF:

0.0204

TwinsUK

AF:

0.0286

AC:

106

ALSPAC

AF:

0.0322

AC:

124

ESP6500AA

AF:

0.00714

AC:

ESP6500EA

AF:

0.0302

AC:

254

ExAC

AF:

0.0238

AC:

2880

Asia WGS

AF:

0.00318

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Dec 13, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 05, 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. -

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 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

Benign

0.11

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.13

T;.;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.026

LIST_S2

Uncertain

0.91

D;D;D;D

MetaRNN

Benign

0.0064

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.97

L;.;L;.

PhyloP100

0.21

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.11

N;N;N;.

REVEL

Benign

0.11

Sift

Benign

0.23

T;T;T;.

Sift4G

Benign

0.12

T;T;T;T

Polyphen

0.16

B;.;.;.

Vest4

0.092

MPC

0.19

ClinPred

0.0073

GERP RS

-7.1

PromoterAI

0.0018

Neutral

(source)

Varity_R

0.039

gMVP

0.46

Mutation Taster

=298/2

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