9-110800863-G-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005592.4(MUSK):c.2485G>T(p.Val829Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0351 in 1,600,684 control chromosomes in the GnomAD database, including 3,194 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.087 ( 1376 hom., cov: 32)

Exomes 𝑓: 0.030 ( 1818 hom. )

Consequence

MUSK
NM_005592.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.441

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020249784).

BP6

Variant 9-110800863-G-T is Benign according to our data. Variant chr9-110800863-G-T is described in ClinVar as [Benign]. Clinvar id is 129633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.24 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUSK	NM_005592.4 link	c.2485G>T	p.Val829Leu	missense_variant	Exon 15 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.2485G>T	p.Val829Leu	missense_variant	Exon 15 of 15	5	NM_005592.4	ENSP00000363571.4	O15146-1
MUSK	ENST00000416899.7 link	c.2461G>T	p.Val821Leu	missense_variant	Exon 14 of 14	5		ENSP00000393608.3	A0A087WSY1
MUSK	ENST00000189978.10 link	c.2227G>T	p.Val743Leu	missense_variant	Exon 14 of 14	5		ENSP00000189978.6	O15146-2

Frequencies

GnomAD3 genomes

AF:

0.0870

AC:

13227

AN:

152090

Hom.:

1373

Cov.:

show subpopulations

Gnomad AFR

AF:

0.244

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.0487

Gnomad ASJ

AF:

0.0536

Gnomad EAS

AF:

0.0282

Gnomad SAS

AF:

0.0625

Gnomad FIN

AF:

0.00641

Gnomad MID

AF:

0.0886

Gnomad NFE

AF:

0.0217

Gnomad OTH

AF:

0.0793

GnomAD3 exomes

AF:

0.0433

AC:

10349

AN:

238816

Hom.:

629

AF XY:

0.0415

AC XY:

5351

AN XY:

129006

show subpopulations

Gnomad AFR exome

AF:

0.246

Gnomad AMR exome

AF:

0.0301

Gnomad ASJ exome

AF:

0.0533

Gnomad EAS exome

AF:

0.0241

Gnomad SAS exome

AF:

0.0677

Gnomad FIN exome

AF:

0.00736

Gnomad NFE exome

AF:

0.0217

Gnomad OTH exome

AF:

0.0425

GnomAD4 exome

AF:

0.0296

AC:

42854

AN:

1448476

Hom.:

1818

Cov.:

AF XY:

0.0303

AC XY:

21767

AN XY:

718872

show subpopulations

Gnomad4 AFR exome

AF:

0.258

Gnomad4 AMR exome

AF:

0.0309

Gnomad4 ASJ exome

AF:

0.0552

Gnomad4 EAS exome

AF:

0.0299

Gnomad4 SAS exome

AF:

0.0673

Gnomad4 FIN exome

AF:

0.00689

Gnomad4 NFE exome

AF:

0.0193

Gnomad4 OTH exome

AF:

0.0428

GnomAD4 genome

AF:

0.0871

AC:

13255

AN:

152208

Hom.:

1376

Cov.:

AF XY:

0.0850

AC XY:

6326

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.244

Gnomad4 AMR

AF:

0.0486

Gnomad4 ASJ

AF:

0.0536

Gnomad4 EAS

AF:

0.0286

Gnomad4 SAS

AF:

0.0617

Gnomad4 FIN

AF:

0.00641

Gnomad4 NFE

AF:

0.0217

Gnomad4 OTH

AF:

0.0814

Alfa

AF:

0.0344

Hom.:

609

Bravo

AF:

0.0971

TwinsUK

AF:

0.0216

AC:

ALSPAC

AF:

0.0176

AC:

ESP6500AA

AF:

0.242

AC:

1001

ESP6500EA

AF:

0.0220

AC:

184

ExAC

AF:

0.0470

AC:

5683

Asia WGS

AF:

0.0550

AC:

192

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Jan 29, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 19, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital myasthenic syndrome 9

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.59

CADD

Benign

0.43

DANN

Benign

0.17

DEOGEN2

Benign

0.17

T;.;.;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.78

T;T;T;T

MetaRNN

Benign

0.0020

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.060

N;.;.;.

PrimateAI

Benign

0.29

PROVEAN

Benign

0.76

N;.;.;.

REVEL

Benign

0.13

Sift

Benign

1.0

T;.;.;.

Sift4G

Benign

0.44

T;T;T;T

Polyphen

0.0

B;.;.;.

Vest4

0.025

MutPred

0.41

Loss of catalytic residue at V829 (P = 0.0802);.;.;.;

MPC

0.16

ClinPred

0.00018

GERP RS

1.5

Varity_R

0.035

gMVP

0.27

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over