Genetic Variant NM_005592.4:c.1031C>G (chr9-110767930-C-G) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3PP5_Moderate

The NM_005592.4(MUSK):c.1031C>G(p.Pro344Arg) 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. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

MUSK
NM_005592.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.38

Publications

11 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.834

PP5

Variant 9-110767930-C-G is Pathogenic according to our data. Variant chr9-110767930-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 30175.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUSK	NM_005592.4 link	c.1031C>G	p.Pro344Arg	missense_variant	Exon 9 of 15	ENST00000374448.9	NP_005583.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MUSK	ENST00000374448.9 link	c.1031C>G	p.Pro344Arg	missense_variant	Exon 9 of 15	5	NM_005592.4	ENSP00000363571.4
MUSK	ENST00000416899.7 link	c.1031C>G	p.Pro344Arg	missense_variant	Exon 9 of 14	5		ENSP00000393608.3
MUSK	ENST00000634612.1 link	n.453C>G		non_coding_transcript_exon_variant	Exon 6 of 6	5
MUSK	ENST00000189978.10 link	c.950+5722C>G		intron_variant	Intron 9 of 13	5		ENSP00000189978.6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Congenital myasthenic syndrome 9

Pathogenic:1

Dec 01, 2009

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

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Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

T;.

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

D;D

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.83

D;D

MetaSVM

Uncertain

0.12

MutationAssessor

Uncertain

2.2

M;.

PhyloP100

7.4

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-3.4

D;.

REVEL

Pathogenic

0.67

Sift

Uncertain

0.0070

D;.

Sift4G

Benign

0.082

T;T

Polyphen

1.0

D;.

Vest4

0.95

MutPred

0.58

Loss of glycosylation at P344 (P = 0.0907);Loss of glycosylation at P344 (P = 0.0907);

MVP

0.90

MPC

0.69

ClinPred

0.99

GERP RS

5.1

Varity_R

0.53

gMVP

0.78

Mutation Taster

=6/94

disease causing (ClinVar)

(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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over