9-110800369-A-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005592.4(MUSK):c.1991A>G(p.Asn664Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.011 in 1,613,820 control chromosomes in the GnomAD database, including 162 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0081 ( 13 hom., cov: 32)

Exomes 𝑓: 0.011 ( 149 hom. )

Consequence

MUSK
NM_005592.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 9.32

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=0.012486756).

BP6

Variant 9-110800369-A-G is Benign according to our data. Variant chr9-110800369-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 259806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-110800369-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00809 (1231/152114) while in subpopulation EAS AF= 0.0141 (73/5166). AF 95% confidence interval is 0.0116. There are 13 homozygotes in gnomad4. There are 554 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUSK	NM_005592.4 link	c.1991A>G	p.Asn664Ser	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.1991A>G	p.Asn664Ser	missense_variant	Exon 15 of 15	5	NM_005592.4	ENSP00000363571.4	O15146-1
MUSK	ENST00000416899.7 link	c.1967A>G	p.Asn656Ser	missense_variant	Exon 14 of 14	5		ENSP00000393608.3	A0A087WSY1
MUSK	ENST00000189978.10 link	c.1733A>G	p.Asn578Ser	missense_variant	Exon 14 of 14	5		ENSP00000189978.6	O15146-2

Frequencies

GnomAD3 genomes

AF:

0.00811

AC:

1232

AN:

151996

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00213

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.00786

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.0141

Gnomad SAS

AF:

0.00977

Gnomad FIN

AF:

0.00368

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0123

Gnomad OTH

AF:

0.00288

GnomAD3 exomes

AF:

0.00833

AC:

2076

AN:

249104

Hom.:

AF XY:

0.00867

AC XY:

1171

AN XY:

135108

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.00446

Gnomad ASJ exome

AF:

0.00278

Gnomad EAS exome

AF:

0.00178

Gnomad SAS exome

AF:

0.00961

Gnomad FIN exome

AF:

0.00418

Gnomad NFE exome

AF:

0.0125

Gnomad OTH exome

AF:

0.00860

GnomAD4 exome

AF:

0.0113

AC:

16491

AN:

1461706

Hom.:

149

Cov.:

AF XY:

0.0112

AC XY:

8165

AN XY:

727134

show subpopulations

Gnomad4 AFR exome

AF:

0.00149

Gnomad4 AMR exome

AF:

0.00429

Gnomad4 ASJ exome

AF:

0.00237

Gnomad4 EAS exome

AF:

0.0280

Gnomad4 SAS exome

AF:

0.00924

Gnomad4 FIN exome

AF:

0.00489

Gnomad4 NFE exome

AF:

0.0121

Gnomad4 OTH exome

AF:

0.00933

GnomAD4 genome

AF:

0.00809

AC:

1231

AN:

152114

Hom.:

Cov.:

AF XY:

0.00745

AC XY:

554

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.00212

Gnomad4 AMR

AF:

0.00785

Gnomad4 ASJ

AF:

0.00231

Gnomad4 EAS

AF:

0.0141

Gnomad4 SAS

AF:

0.00957

Gnomad4 FIN

AF:

0.00368

Gnomad4 NFE

AF:

0.0123

Gnomad4 OTH

AF:

0.00285

Alfa

AF:

0.0106

Hom.:

Bravo

AF:

0.00759

TwinsUK

AF:

0.0124

AC:

ALSPAC

AF:

0.0143

AC:

ESP6500AA

AF:

0.00423

AC:

ESP6500EA

AF:

0.0130

AC:

110

ExAC

AF:

0.00858

AC:

1039

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.0106

EpiControl

AF:

0.0119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Apr 07, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 29, 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. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MUSK: BS1, BS2 -

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

Benign:2

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 02, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital myasthenic syndrome 9

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

T;.;.;.

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D;D

MetaRNN

Benign

0.012

T;T;T;T

MetaSVM

Uncertain

-0.26

MutationAssessor

Benign

0.74

N;.;.;.

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.5

D;.;.;.

REVEL

Uncertain

0.44

Sift

Benign

0.081

T;.;.;.

Sift4G

Benign

0.077

T;T;D;D

Polyphen

0.47

P;.;.;.

Vest4

0.69

MVP

0.84

MPC

0.54

ClinPred

0.026

GERP RS

5.2

Varity_R

0.38

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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