Genetic Variant MUSK:p.Ile575Asn (chr9-110785664-T-A) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_005592.4(MUSK):c.1724T>A(p.Ile575Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. I575T) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 31)

Consequence

MUSK
NM_005592.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.67

Publications

8 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)
fetal akinesia deformation sequence 1
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
postsynaptic congenital myasthenic syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

MUSK links:

LOC107987115 (HGNC:):

LOC107987115 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-110785664-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 190467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.943

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	UniProt
MUSK	NM_005592.4	MANE Select	c.1724T>A	p.Ile575Asn	missense	Exon 13 of 15	NP_005583.1	O15146-1
MUSK	NM_001166280.2		c.1466T>A	p.Ile489Asn	missense	Exon 12 of 14	NP_001159752.1	O15146-2
MUSK	NM_001166281.2		c.1436T>A	p.Ile479Asn	missense	Exon 11 of 13	NP_001159753.1	O15146-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MUSK	ENST00000374448.9	TSL:5 MANE Select	c.1724T>A	p.Ile575Asn	missense	Exon 13 of 15	ENSP00000363571.4	O15146-1
MUSK	ENST00000416899.7	TSL:5	c.1700T>A	p.Ile567Asn	missense	Exon 12 of 14	ENSP00000393608.3	A0A087WSY1
MUSK	ENST00000189978.10	TSL:5	c.1466T>A	p.Ile489Asn	missense	Exon 12 of 14	ENSP00000189978.6	O15146-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000402

AC:

AN:

248956

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000827

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.53

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.94

MetaSVM

Pathogenic

0.80

MutationAssessor

Uncertain

2.8

PhyloP100

7.7

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-6.6

REVEL

Pathogenic

0.83

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.96

MutPred

0.76

Gain of disorder (P = 0.014)

MVP

0.97

MPC

0.93

ClinPred

1.0

GERP RS

5.9

Varity_R

0.93

gMVP

0.89

Mutation Taster

=21/79

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over