9-110695519-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005592.4(MUSK):ā€‹c.475A>Gā€‹(p.Ser159Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 1,555,198 control chromosomes in the GnomAD database, including 20,579 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.12 ( 1533 hom., cov: 32)
Exomes š‘“: 0.16 ( 19046 hom. )

Consequence

MUSK
NM_005592.4 missense

Scores

1
17

Clinical Significance

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

Conservation

PhyloP100: 1.62
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]

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=0.0034041703).
BP6
Variant 9-110695519-A-G is Benign according to our data. Variant chr9-110695519-A-G is described in ClinVar as [Benign]. Clinvar id is 129636.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.19 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MUSKNM_005592.4 linkuse as main transcriptc.475A>G p.Ser159Gly missense_variant 4/15 ENST00000374448.9 NP_005583.1 O15146-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MUSKENST00000374448.9 linkuse as main transcriptc.475A>G p.Ser159Gly missense_variant 4/155 NM_005592.4 ENSP00000363571.4 O15146-1
MUSKENST00000416899.7 linkuse as main transcriptc.475A>G p.Ser159Gly missense_variant 4/145 ENSP00000393608.3 A0A087WSY1
MUSKENST00000189978.10 linkuse as main transcriptc.475A>G p.Ser159Gly missense_variant 4/145 ENSP00000189978.6 O15146-2
MUSKENST00000374439.1 linkuse as main transcriptc.169A>G p.Ser57Gly missense_variant 2/45 ENSP00000363562.2 F6XAJ2

Frequencies

GnomAD3 genomes
AF:
0.124
AC:
18932
AN:
152156
Hom.:
1528
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0276
Gnomad AMI
AF:
0.164
Gnomad AMR
AF:
0.0804
Gnomad ASJ
AF:
0.164
Gnomad EAS
AF:
0.200
Gnomad SAS
AF:
0.149
Gnomad FIN
AF:
0.250
Gnomad MID
AF:
0.0949
Gnomad NFE
AF:
0.165
Gnomad OTH
AF:
0.0981
GnomAD3 exomes
AF:
0.148
AC:
26461
AN:
178208
Hom.:
2252
AF XY:
0.152
AC XY:
14303
AN XY:
94378
show subpopulations
Gnomad AFR exome
AF:
0.0239
Gnomad AMR exome
AF:
0.0613
Gnomad ASJ exome
AF:
0.169
Gnomad EAS exome
AF:
0.199
Gnomad SAS exome
AF:
0.150
Gnomad FIN exome
AF:
0.244
Gnomad NFE exome
AF:
0.161
Gnomad OTH exome
AF:
0.148
GnomAD4 exome
AF:
0.161
AC:
225809
AN:
1402922
Hom.:
19046
Cov.:
29
AF XY:
0.161
AC XY:
111801
AN XY:
693436
show subpopulations
Gnomad4 AFR exome
AF:
0.0231
Gnomad4 AMR exome
AF:
0.0629
Gnomad4 ASJ exome
AF:
0.165
Gnomad4 EAS exome
AF:
0.186
Gnomad4 SAS exome
AF:
0.148
Gnomad4 FIN exome
AF:
0.237
Gnomad4 NFE exome
AF:
0.166
Gnomad4 OTH exome
AF:
0.150
GnomAD4 genome
AF:
0.124
AC:
18941
AN:
152276
Hom.:
1533
Cov.:
32
AF XY:
0.128
AC XY:
9534
AN XY:
74452
show subpopulations
Gnomad4 AFR
AF:
0.0275
Gnomad4 AMR
AF:
0.0802
Gnomad4 ASJ
AF:
0.164
Gnomad4 EAS
AF:
0.200
Gnomad4 SAS
AF:
0.150
Gnomad4 FIN
AF:
0.250
Gnomad4 NFE
AF:
0.165
Gnomad4 OTH
AF:
0.102
Alfa
AF:
0.134
Hom.:
1206
Bravo
AF:
0.107
TwinsUK
AF:
0.177
AC:
657
ALSPAC
AF:
0.172
AC:
662
ESP6500AA
AF:
0.0330
AC:
120
ESP6500EA
AF:
0.154
AC:
1249
ExAC
AF:
0.119
AC:
13958
Asia WGS
AF:
0.155
AC:
539
AN:
3474

ClinVar

Significance: Benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
Benign, criteria provided, single submitterclinical testingGeneDxFeb 19, 2016This 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 submitterclinical testingGenetic Services Laboratory, University of ChicagoAug 15, 2013- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
not provided Benign:1
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Fetal akinesia deformation sequence 1;C4225368:Congenital myasthenic syndrome 9 Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
Congenital myasthenic syndrome 9 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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
0.20
BayesDel_addAF
Benign
-0.65
T
BayesDel_noAF
Benign
-0.56
CADD
Benign
13
DANN
Uncertain
0.98
DEOGEN2
Benign
0.095
T;.;.;.;.
Eigen
Benign
-0.80
Eigen_PC
Benign
-0.69
FATHMM_MKL
Benign
0.081
N
LIST_S2
Benign
0.80
T;T;T;T;T
MetaRNN
Benign
0.0034
T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
-0.34
N;.;N;.;.
PrimateAI
Benign
0.37
T
PROVEAN
Benign
-0.78
N;N;N;.;.
REVEL
Benign
0.061
Sift
Benign
0.32
T;T;T;.;.
Sift4G
Benign
0.38
T;T;T;T;T
Polyphen
0.0020
B;.;.;.;.
Vest4
0.045
MPC
0.15
ClinPred
0.0031
T
GERP RS
3.4
Varity_R
0.17
gMVP
0.31

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.

Other links and lift over

dbSNP: rs35176182; hg19: chr9-113457799; COSMIC: COSV51881440; API