Genetic Variant MUSK:p.Arg162Ser (chr9-110695530-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_005592.4(MUSK):c.486G>T(p.Arg162Ser) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. R162R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MUSK
NM_005592.4 missense, splice_region

Scores

Splicing: ADA: 0.9997

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.73

Publications

0 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 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005592.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MUSK	NM_005592.4	MANE Select	c.486G>T	p.Arg162Ser	missense splice_region	Exon 4 of 15	NP_005583.1
MUSK	NM_001166280.2		c.486G>T	p.Arg162Ser	missense splice_region	Exon 4 of 14	NP_001159752.1
MUSK	NM_001166281.2		c.486G>T	p.Arg162Ser	missense splice_region	Exon 4 of 13	NP_001159753.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MUSK	ENST00000374448.9	TSL:5 MANE Select	c.486G>T	p.Arg162Ser	missense splice_region	Exon 4 of 15	ENSP00000363571.4
MUSK	ENST00000416899.7	TSL:5	c.486G>T	p.Arg162Ser	missense splice_region	Exon 4 of 14	ENSP00000393608.3
MUSK	ENST00000189978.10	TSL:5	c.486G>T	p.Arg162Ser	missense splice_region	Exon 4 of 14	ENSP00000189978.6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1396976

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

689874

African (AFR)

AF:

0.00

AC:

AN:

31568

American (AMR)

AF:

0.00

AC:

AN:

35304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25044

East Asian (EAS)

AF:

0.00

AC:

AN:

36658

South Asian (SAS)

AF:

0.00

AC:

AN:

76648

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5690

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1077552

Other (OTH)

AF:

0.00

AC:

AN:

58130

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Benign

0.0093

BayesDel_noAF

Benign

-0.22

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

Eigen

Benign

0.13

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.032

MetaRNN

Benign

0.35

MetaSVM

Benign

-0.67

MutationAssessor

Benign

0.46

PhyloP100

4.7

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.84

REVEL

Benign

0.17

Sift

Benign

0.064

Sift4G

Uncertain

0.033

Polyphen

0.42

Vest4

0.43

MutPred

0.56

Gain of disorder (P = 0.07)

MVP

0.75

MPC

0.23

ClinPred

0.58

GERP RS

6.0

Varity_R

0.27

gMVP

0.50

Mutation Taster

=58/42

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.97

SpliceAI score (max)

0.020

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over