rs55786136

Positions:

chr9-110687230-G-A

Variant summary

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

The NM_005592.4(MUSK):c.320G>A(p.Gly107Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00326 in 1,613,842 control chromosomes in the GnomAD database, including 11 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0033 ( 11 hom. )

Consequence

MUSK
NM_005592.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.03

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 5 pathogenic changes around while only 0 benign (100%) in NM_005592.4

BP4

Computational evidence support a benign effect (MetaRNN=0.0066536367).

BP6

Variant 9-110687230-G-A is Benign according to our data. Variant chr9-110687230-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 259809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00325 (495/152274) while in subpopulation NFE AF= 0.00393 (267/68024). AF 95% confidence interval is 0.00354. There are 0 homozygotes in gnomad4. There are 282 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUSK	NM_005592.4 linkuse as main transcript	c.320G>A	p.Gly107Glu	missense_variant	3/15	ENST00000374448.9	NP_005583.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUSK	ENST00000374448.9 linkuse as main transcript	c.320G>A	p.Gly107Glu	missense_variant	3/15	5	NM_005592.4	ENSP00000363571	P4	O15146-1
MUSK	ENST00000416899.7 linkuse as main transcript	c.320G>A	p.Gly107Glu	missense_variant	3/14	5		ENSP00000393608	A1
MUSK	ENST00000189978.10 linkuse as main transcript	c.320G>A	p.Gly107Glu	missense_variant	3/14	5		ENSP00000189978		O15146-2
MUSK	ENST00000374439.1 linkuse as main transcript	c.14G>A	p.Gly5Glu	missense_variant	1/4	5		ENSP00000363562

Frequencies

GnomAD3 genomes

AF:

0.00325

AC:

494

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.00275

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.0139

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00392

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00350

AC:

873

AN:

249238

Hom.:

AF XY:

0.00341

AC XY:

461

AN XY:

135212

show subpopulations

Gnomad AFR exome

AF:

0.000517

Gnomad AMR exome

AF:

0.00145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000229

Gnomad FIN exome

AF:

0.0129

Gnomad NFE exome

AF:

0.00450

Gnomad OTH exome

AF:

0.00363

GnomAD4 exome

AF:

0.00326

AC:

4770

AN:

1461568

Hom.:

Cov.:

AF XY:

0.00320

AC XY:

2328

AN XY:

727060

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.00150

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000232

Gnomad4 FIN exome

AF:

0.0126

Gnomad4 NFE exome

AF:

0.00340

Gnomad4 OTH exome

AF:

0.00295

GnomAD4 genome

AF:

0.00325

AC:

495

AN:

152274

Hom.:

Cov.:

AF XY:

0.00379

AC XY:

282

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.000457

Gnomad4 AMR

AF:

0.00275

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.0139

Gnomad4 NFE

AF:

0.00393

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00330

Hom.:

Bravo

AF:

0.00226

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000491

AC:

ESP6500EA

AF:

0.00369

AC:

ExAC

AF:

0.00366

AC:

443

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00322

EpiControl

AF:

0.00356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	MUSK: BP4, BS1 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

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

0.12

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Benign

0.52

DEOGEN2

Benign

0.062

T;.;.;.;.

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.19

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.85

T;T;T;T;T

MetaRNN

Benign

0.0067

T;T;T;T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

-1.0

N;.;N;.;.

MutationTaster

Benign

0.93

D;D;D;D;D

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.28

N;N;N;.;.

REVEL

Benign

0.18

Sift

Benign

0.54

T;T;T;.;.

Sift4G

Benign

1.0

T;T;T;T;T

Polyphen

0.0

B;.;.;.;.

Vest4

0.18

MVP

0.68

MPC

0.21

ClinPred

0.013

GERP RS

4.1

Varity_R

0.077

gMVP

0.56

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