rs34115159

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2BP4_StrongBP6_Very_StrongBS1

The NM_005592.4(MUSK):c.2573G>A(p.Arg858His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000455 in 1,523,288 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R858C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00045 ( 1 hom. )

Consequence

MUSK
NM_005592.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 9.92

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 -14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.008609474).

BP6

Variant 9-110800951-G-A is Benign according to our data. Variant chr9-110800951-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 364617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000486 (74/152334) while in subpopulation EAS AF= 0.0137 (71/5184). AF 95% confidence interval is 0.0111. There are 0 homozygotes in gnomad4. There are 44 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUSK	NM_005592.4 linkuse as main transcript	c.2573G>A	p.Arg858His	missense_variant	15/15	ENST00000374448.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUSK	ENST00000374448.9 linkuse as main transcript	c.2573G>A	p.Arg858His	missense_variant	15/15	5	NM_005592.4	P4	O15146-1
MUSK	ENST00000416899.7 linkuse as main transcript	c.2549G>A	p.Arg850His	missense_variant	14/14	5		A1
MUSK	ENST00000189978.10 linkuse as main transcript	c.2315G>A	p.Arg772His	missense_variant	14/14	5			O15146-2

Frequencies

GnomAD3 genomes

AF:

0.000486

AC:

AN:

152216

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:

0.0137

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00136

AC:

242

AN:

177776

Hom.:

AF XY:

0.00130

AC XY:

122

AN XY:

93858

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0149

Gnomad SAS exome

AF:

0.0000678

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000577

Gnomad OTH exome

AF:

0.000991

GnomAD4 exome

AF:

0.000452

AC:

619

AN:

1370954

Hom.:

Cov.:

AF XY:

0.000435

AC XY:

292

AN XY:

672028

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0139

Gnomad4 SAS exome

AF:

0.000157

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000243

Gnomad4 OTH exome

AF:

0.000692

GnomAD4 genome

AF:

0.000486

AC:

AN:

152334

Hom.:

Cov.:

AF XY:

0.000591

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0137

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000433

Hom.:

Bravo

AF:

0.000495

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.00109

AC:

128

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

MUSK-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 01, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Congenital myasthenic syndrome 9

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.020

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Benign

0.20

T;.;.;.

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;D;D

MetaRNN

Benign

0.0086

T;T;T;T

MetaSVM

Uncertain

-0.14

MutationAssessor

Benign

0.66

N;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-2.0

N;.;.;.

REVEL

Uncertain

0.40

Sift

Uncertain

0.026

D;.;.;.

Sift4G

Benign

0.089

T;T;D;T

Polyphen

1.0

D;.;.;.

Vest4

0.73

MVP

0.92

MPC

0.77

ClinPred

0.11

GERP RS

5.6

Varity_R

0.28

gMVP

0.61

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