Genetic Variant MUSK:p.Ser159Cys (chr9-110695519-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005592.4(MUSK):c.475A>T(p.Ser159Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S159G) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MUSK
NM_005592.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.62

Publications

23 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17578927).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUSK	NM_005592.4 link	c.475A>T	p.Ser159Cys	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.475A>T	p.Ser159Cys	missense_variant	Exon 4 of 15	5	NM_005592.4	ENSP00000363571.4	O15146-1
MUSK	ENST00000416899.7 link	c.475A>T	p.Ser159Cys	missense_variant	Exon 4 of 14	5		ENSP00000393608.3	A0A087WSY1
MUSK	ENST00000189978.10 link	c.475A>T	p.Ser159Cys	missense_variant	Exon 4 of 14	5		ENSP00000189978.6	O15146-2
MUSK	ENST00000374439.1 link	c.169A>T	p.Ser57Cys	missense_variant	Exon 2 of 4	5		ENSP00000363562.2	F6XAJ2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1406512

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

695130

African (AFR)

AF:

0.00

AC:

AN:

32078

American (AMR)

AF:

0.00

AC:

AN:

37424

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25248

East Asian (EAS)

AF:

0.00

AC:

AN:

37204

South Asian (SAS)

AF:

0.00

AC:

AN:

78668

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50726

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1080998

Other (OTH)

AF:

0.00

AC:

AN:

58468

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

1578

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.35

T;.;.;.;.

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.27

LIST_S2

Uncertain

0.94

D;D;D;D;T

M_CAP

Benign

0.037

MetaRNN

Benign

0.18

T;T;T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Uncertain

2.4

M;.;M;.;.

PhyloP100

1.6

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.3

N;N;N;.;.

REVEL

Benign

0.088

Sift

Benign

0.046

D;D;T;.;.

Sift4G

Uncertain

0.054

T;T;T;T;T

Polyphen

0.073

B;.;.;.;.

Vest4

0.27

MutPred

0.52

Loss of disorder (P = 7e-04);Loss of disorder (P = 7e-04);Loss of disorder (P = 7e-04);Loss of disorder (P = 7e-04);.;

MVP

0.74

MPC

0.19

ClinPred

0.30

GERP RS

3.4

Varity_R

0.23

gMVP

0.36

Mutation Taster

=97/3

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over