chr9-110800309-T-C

Position:

chr9-110800309-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_005592.4(MUSK):c.1931T>C(p.Val644Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00357 in 1,604,290 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0027 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0037 ( 15 hom. )

Consequence

MUSK
NM_005592.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:6

Conservation

PhyloP100: 7.95

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.057576776).

BP6

Variant 9-110800309-T-C is Benign according to our data. Variant chr9-110800309-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 259805.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=6}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00266 (404/151880) while in subpopulation SAS AF= 0.00461 (22/4772). AF 95% confidence interval is 0.00363. There are 3 homozygotes in gnomad4. There are 216 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUSK	NM_005592.4 link	c.1931T>C	p.Val644Ala	missense_variant	15/15	ENST00000374448.9	NP_005583.1	O15146-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MUSK	ENST00000374448.9 link	c.1931T>C	p.Val644Ala	missense_variant	15/15	5	NM_005592.4	ENSP00000363571.4	O15146-1
MUSK	ENST00000416899.7 link	c.1907T>C	p.Val636Ala	missense_variant	14/14	5		ENSP00000393608.3	A0A087WSY1
MUSK	ENST00000189978.10 link	c.1673T>C	p.Val558Ala	missense_variant	14/14	5		ENSP00000189978.6	O15146-2

Frequencies

GnomAD3 genomes

AF:

0.00266

AC:

404

AN:

151762

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000388

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00321

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00461

Gnomad FIN

AF:

0.00274

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00402

Gnomad OTH

AF:

0.00336

GnomAD3 exomes

AF:

0.00298

AC:

730

AN:

245278

Hom.:

AF XY:

0.00322

AC XY:

428

AN XY:

132922

show subpopulations

Gnomad AFR exome

AF:

0.000259

Gnomad AMR exome

AF:

0.00158

Gnomad ASJ exome

AF:

0.00145

Gnomad EAS exome

AF:

0.0000557

Gnomad SAS exome

AF:

0.00368

Gnomad FIN exome

AF:

0.00269

Gnomad NFE exome

AF:

0.00427

Gnomad OTH exome

AF:

0.00268

GnomAD4 exome

AF:

0.00367

AC:

5329

AN:

1452410

Hom.:

Cov.:

AF XY:

0.00364

AC XY:

2627

AN XY:

720868

show subpopulations

Gnomad4 AFR exome

AF:

0.000330

Gnomad4 AMR exome

AF:

0.00182

Gnomad4 ASJ exome

AF:

0.00160

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00351

Gnomad4 FIN exome

AF:

0.00258

Gnomad4 NFE exome

AF:

0.00411

Gnomad4 OTH exome

AF:

0.00319

GnomAD4 genome

AF:

0.00266

AC:

404

AN:

151880

Hom.:

Cov.:

AF XY:

0.00291

AC XY:

216

AN XY:

74248

show subpopulations

Gnomad4 AFR

AF:

0.000386

Gnomad4 AMR

AF:

0.00321

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00461

Gnomad4 FIN

AF:

0.00274

Gnomad4 NFE

AF:

0.00402

Gnomad4 OTH

AF:

0.00332

Alfa

AF:

0.00322

Hom.:

Bravo

AF:

0.00284

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000481

AC:

ESP6500EA

AF:

0.00344

AC:

ExAC

AF:

0.00273

AC:

330

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 03, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Mar 22, 2021	BS1 -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	MUSK: BS2 -

not specified

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 08, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 25, 2015	- -

Congenital myasthenic syndrome 9

Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 03, 2025

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.68

BayesDel_addAF

Benign

0.0069

BayesDel_noAF

Pathogenic

0.24

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.48

T;.;.;.

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.77

T;T;T;T

M_CAP

Uncertain

0.097

MetaRNN

Benign

0.058

T;T;T;T

MetaSVM

Uncertain

-0.068

MutationAssessor

Benign

1.4

L;.;.;.

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-3.7

D;.;.;.

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0020

D;.;.;.

Sift4G

Uncertain

0.0030

D;D;D;D

Polyphen

0.37

B;.;.;.

Vest4

0.87

MVP

0.85

MPC

0.76

ClinPred

0.036

GERP RS

5.1

Varity_R

0.58

gMVP

0.69

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