rs202239254

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_005592.4(MUSK):c.1360G>A(p.Asp454Asn) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000373 in 1,607,446 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

MUSK
NM_005592.4 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2O:1

Conservation

PhyloP100: 8.54

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:

LOC107987115 (HGNC:):

LOC107987115 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 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, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUSK	NM_005592.4 link	c.1360G>A	p.Asp454Asn	missense_variant, splice_region_variant	Exon 10 of 15	ENST00000374448.9	NP_005583.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MUSK	ENST00000374448.9 link	c.1360G>A	p.Asp454Asn	missense_variant, splice_region_variant	Exon 10 of 15	5	NM_005592.4	ENSP00000363571.4
MUSK	ENST00000416899.7 link	c.1360G>A	p.Ala454Thr	missense_variant, splice_region_variant	Exon 10 of 14	5		ENSP00000393608.3
MUSK	ENST00000189978.10 link	c.1126G>A	p.Ala376Thr	missense_variant, splice_region_variant	Exon 10 of 14	5		ENSP00000189978.6
MUSK	ENST00000374438.1 link	n.617G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000204

AC:

AN:

244782

AF XY:

0.0000301

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000103

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000361

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000399

AC:

AN:

1455286

Hom.:

Cov.:

AF XY:

0.0000484

AC XY:

AN XY:

723122

show subpopulations

African (AFR)

AF:

0.0000301

AC:

AN:

33258

American (AMR)

AF:

0.00

AC:

AN:

44130

Ashkenazi Jewish (ASJ)

AF:

0.0000775

AC:

AN:

25814

East Asian (EAS)

AF:

0.00

AC:

AN:

39560

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85454

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53246

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.0000469

AC:

AN:

1108026

Other (OTH)

AF:

0.0000333

AC:

AN:

60072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152160

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41432

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000774

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fetal akinesia deformation sequence 1;C4225368:Congenital myasthenic syndrome 9

Uncertain:1Other:1

Jul 06, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 454 of the MUSK protein (p.Asp454Asn). This variant also falls at the last nucleotide of exon 10, which is part of the consensus splice site for this exon. This variant is present in population databases (rs202239254, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with MUSK-related conditions. ClinVar contains an entry for this variant (Variation ID: 542742). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

GenomeConnect - Invitae Patient Insights Network

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant classified as Uncertain significance and reported on 12-04-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

MUSK-related disorder

Uncertain:1

Feb 09, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The MUSK c.1360G>A variant is predicted to result in the amino acid substitution p.Asp454Asn. This variant occurs at the last nucleotide position of exon 10 and is predicted to impact splicing based on available splicing prediction programs (Alamut Visual Plus v1.6.1). However, the use of computer prediction programs is not equivalent to functional evidence. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.010% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-113538243-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Benign

-0.20

CADD

Pathogenic

(source)

DANN

Benign

0.96

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.80

T;T;T

M_CAP

Benign

0.017

MetaRNN

Benign

0.29

T;T;T

MetaSVM

Benign

-0.56

PhyloP100

8.5

PROVEAN

Benign

1.6

N;D;.

REVEL

Benign

0.16

Sift

Benign

1.0

T;D;.

Sift4G

Benign

0.59

T;T;T

Vest4

0.60

MVP

0.74

ClinPred

0.79

GERP RS

5.7

Varity_R

0.14

Mutation Taster

=47/53

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.98

SpliceAI score (max)

0.82

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.37

Position offset: 30

DS_DL_spliceai

0.82

Position offset: 0

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over