rs35142681

Positions:

chr9-110687209-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_005592.4(MUSK):c.299C>T(p.Thr100Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0269 in 1,613,722 control chromosomes in the GnomAD database, including 711 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 (★★). Synonymous variant affecting the same amino acid position (i.e. T100T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.021 ( 44 hom., cov: 31)

Exomes 𝑓: 0.027 ( 667 hom. )

Consequence

MUSK
NM_005592.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.213

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 -18 ACMG points.

PM1

In a domain Ig-like 1 (size 88) in uniprot entity MUSK_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_005592.4

BP4

Computational evidence support a benign effect (MetaRNN=0.0064065754).

BP6

Variant 9-110687209-C-T is Benign according to our data. Variant chr9-110687209-C-T is described in ClinVar as [Benign]. Clinvar id is 129634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-110687209-C-T is described in Lovd as [Benign]. Variant chr9-110687209-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0213 (3236/152218) while in subpopulation NFE AF= 0.0324 (2206/68016). AF 95% confidence interval is 0.0313. There are 44 homozygotes in gnomad4. There are 1504 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 44 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUSK	NM_005592.4 linkuse as main transcript	c.299C>T	p.Thr100Met	missense_variant	3/15	ENST00000374448.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUSK	ENST00000374448.9 linkuse as main transcript	c.299C>T	p.Thr100Met	missense_variant	3/15	5	NM_005592.4	P4	O15146-1
MUSK	ENST00000416899.7 linkuse as main transcript	c.299C>T	p.Thr100Met	missense_variant	3/14	5		A1
MUSK	ENST00000189978.10 linkuse as main transcript	c.299C>T	p.Thr100Met	missense_variant	3/14	5			O15146-2
MUSK	ENST00000374439.1 linkuse as main transcript			upstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0213

AC:

3236

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00625

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.0191

Gnomad ASJ

AF:

0.0259

Gnomad EAS

AF:

0.00174

Gnomad SAS

AF:

0.00311

Gnomad FIN

AF:

0.0290

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0324

Gnomad OTH

AF:

0.0196

GnomAD3 exomes

AF:

0.0230

AC:

5741

AN:

249182

Hom.:

107

AF XY:

0.0230

AC XY:

3108

AN XY:

135186

show subpopulations

Gnomad AFR exome

AF:

0.00568

Gnomad AMR exome

AF:

0.0123

Gnomad ASJ exome

AF:

0.0276

Gnomad EAS exome

AF:

0.00362

Gnomad SAS exome

AF:

0.00451

Gnomad FIN exome

AF:

0.0310

Gnomad NFE exome

AF:

0.0348

Gnomad OTH exome

AF:

0.0246

GnomAD4 exome

AF:

0.0274

AC:

40103

AN:

1461504

Hom.:

667

Cov.:

AF XY:

0.0269

AC XY:

19524

AN XY:

727020

show subpopulations

Gnomad4 AFR exome

AF:

0.00463

Gnomad4 AMR exome

AF:

0.0125

Gnomad4 ASJ exome

AF:

0.0253

Gnomad4 EAS exome

AF:

0.00146

Gnomad4 SAS exome

AF:

0.00450

Gnomad4 FIN exome

AF:

0.0309

Gnomad4 NFE exome

AF:

0.0315

Gnomad4 OTH exome

AF:

0.0252

GnomAD4 genome

AF:

0.0213

AC:

3236

AN:

152218

Hom.:

Cov.:

AF XY:

0.0202

AC XY:

1504

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.00623

Gnomad4 AMR

AF:

0.0190

Gnomad4 ASJ

AF:

0.0259

Gnomad4 EAS

AF:

0.00174

Gnomad4 SAS

AF:

0.00311

Gnomad4 FIN

AF:

0.0290

Gnomad4 NFE

AF:

0.0324

Gnomad4 OTH

AF:

0.0199

Alfa

AF:

0.0289

Hom.:

128

Bravo

AF:

0.0204

TwinsUK

AF:

0.0286

AC:

106

ALSPAC

AF:

0.0322

AC:

124

ESP6500AA

AF:

0.00714

AC:

ESP6500EA

AF:

0.0302

AC:

254

ExAC

AF:

0.0238

AC:

2880

Asia WGS

AF:

0.00318

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 13, 2019	- -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 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

0.11

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Benign

0.13

T;.;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.026

LIST_S2

Uncertain

0.91

D;D;D;D

MetaRNN

Benign

0.0064

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.97

L;.;L;.

MutationTaster

Benign

0.53

D;N;N;N

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.11

N;N;N;.

REVEL

Benign

0.11

Sift

Benign

0.23

T;T;T;.

Sift4G

Benign

0.12

T;T;T;T

Polyphen

0.16

B;.;.;.

Vest4

0.092

MPC

0.19

ClinPred

0.0073

GERP RS

-7.1

Varity_R

0.039

gMVP

0.46

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