9-110800369-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005592.4(MUSK):​c.1991A>G​(p.Asn664Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.011 in 1,613,820 control chromosomes in the GnomAD database, including 162 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0081 ( 13 hom., cov: 32)
Exomes 𝑓: 0.011 ( 149 hom. )

Consequence

MUSK
NM_005592.4 missense

Scores

2
8
8

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 9.32
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=0.012486756).
BP6
Variant 9-110800369-A-G is Benign according to our data. Variant chr9-110800369-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 259806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-110800369-A-G is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00809 (1231/152114) while in subpopulation EAS AF= 0.0141 (73/5166). AF 95% confidence interval is 0.0116. There are 13 homozygotes in gnomad4. There are 554 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MUSKNM_005592.4 linkc.1991A>G p.Asn664Ser missense_variant Exon 15 of 15 ENST00000374448.9 NP_005583.1 O15146-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MUSKENST00000374448.9 linkc.1991A>G p.Asn664Ser missense_variant Exon 15 of 15 5 NM_005592.4 ENSP00000363571.4 O15146-1
MUSKENST00000416899.7 linkc.1967A>G p.Asn656Ser missense_variant Exon 14 of 14 5 ENSP00000393608.3 A0A087WSY1
MUSKENST00000189978.10 linkc.1733A>G p.Asn578Ser missense_variant Exon 14 of 14 5 ENSP00000189978.6 O15146-2

Frequencies

GnomAD3 genomes
AF:
0.00811
AC:
1232
AN:
151996
Hom.:
13
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00213
Gnomad AMI
AF:
0.0110
Gnomad AMR
AF:
0.00786
Gnomad ASJ
AF:
0.00231
Gnomad EAS
AF:
0.0141
Gnomad SAS
AF:
0.00977
Gnomad FIN
AF:
0.00368
Gnomad MID
AF:
0.0158
Gnomad NFE
AF:
0.0123
Gnomad OTH
AF:
0.00288
GnomAD3 exomes
AF:
0.00833
AC:
2076
AN:
249104
Hom.:
14
AF XY:
0.00867
AC XY:
1171
AN XY:
135108
show subpopulations
Gnomad AFR exome
AF:
0.00123
Gnomad AMR exome
AF:
0.00446
Gnomad ASJ exome
AF:
0.00278
Gnomad EAS exome
AF:
0.00178
Gnomad SAS exome
AF:
0.00961
Gnomad FIN exome
AF:
0.00418
Gnomad NFE exome
AF:
0.0125
Gnomad OTH exome
AF:
0.00860
GnomAD4 exome
AF:
0.0113
AC:
16491
AN:
1461706
Hom.:
149
Cov.:
32
AF XY:
0.0112
AC XY:
8165
AN XY:
727134
show subpopulations
Gnomad4 AFR exome
AF:
0.00149
Gnomad4 AMR exome
AF:
0.00429
Gnomad4 ASJ exome
AF:
0.00237
Gnomad4 EAS exome
AF:
0.0280
Gnomad4 SAS exome
AF:
0.00924
Gnomad4 FIN exome
AF:
0.00489
Gnomad4 NFE exome
AF:
0.0121
Gnomad4 OTH exome
AF:
0.00933
GnomAD4 genome
AF:
0.00809
AC:
1231
AN:
152114
Hom.:
13
Cov.:
32
AF XY:
0.00745
AC XY:
554
AN XY:
74378
show subpopulations
Gnomad4 AFR
AF:
0.00212
Gnomad4 AMR
AF:
0.00785
Gnomad4 ASJ
AF:
0.00231
Gnomad4 EAS
AF:
0.0141
Gnomad4 SAS
AF:
0.00957
Gnomad4 FIN
AF:
0.00368
Gnomad4 NFE
AF:
0.0123
Gnomad4 OTH
AF:
0.00285
Alfa
AF:
0.0106
Hom.:
10
Bravo
AF:
0.00759
TwinsUK
AF:
0.0124
AC:
46
ALSPAC
AF:
0.0143
AC:
55
ESP6500AA
AF:
0.00423
AC:
18
ESP6500EA
AF:
0.0130
AC:
110
ExAC
AF:
0.00858
AC:
1039
Asia WGS
AF:
0.00375
AC:
13
AN:
3478
EpiCase
AF:
0.0106
EpiControl
AF:
0.0119

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:2
Apr 07, 2016
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 29, 2016
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

not provided Benign:2
-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Jul 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

MUSK: BS1, BS2 -

Fetal akinesia deformation sequence 1;C4225368:Congenital myasthenic syndrome 9 Benign:2
Feb 01, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 02, 2022
Fulgent Genetics, Fulgent Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Congenital myasthenic syndrome 9 Benign:1
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.22
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.32
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.45
T;.;.;.
Eigen
Uncertain
0.30
Eigen_PC
Uncertain
0.41
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D;D;D;D
MetaRNN
Benign
0.012
T;T;T;T
MetaSVM
Uncertain
-0.26
T
MutationAssessor
Benign
0.74
N;.;.;.
PrimateAI
Uncertain
0.62
T
PROVEAN
Uncertain
-3.5
D;.;.;.
REVEL
Uncertain
0.44
Sift
Benign
0.081
T;.;.;.
Sift4G
Benign
0.077
T;T;D;D
Polyphen
0.47
P;.;.;.
Vest4
0.69
MVP
0.84
MPC
0.54
ClinPred
0.026
T
GERP RS
5.2
Varity_R
0.38
gMVP
0.46

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs55963442; hg19: chr9-113562649; COSMIC: COSV99079049; API