rs199811263

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_005592.4(MUSK):​c.1951A>C​(p.Met651Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000208 in 1,610,786 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

MUSK
NM_005592.4 missense

Scores

5
14

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 5.12
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 -7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.038600177).
BP6
Variant 9-110800329-A-C is Benign according to our data. Variant chr9-110800329-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 570516.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000263 (40/152148) while in subpopulation NFE AF= 0.000368 (25/67994). AF 95% confidence interval is 0.000255. There are 0 homozygotes in gnomad4. There are 22 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MUSKNM_005592.4 linkc.1951A>C p.Met651Leu 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.1951A>C p.Met651Leu missense_variant Exon 15 of 15 5 NM_005592.4 ENSP00000363571.4 O15146-1
MUSKENST00000416899.7 linkc.1927A>C p.Met643Leu missense_variant Exon 14 of 14 5 ENSP00000393608.3 A0A087WSY1
MUSKENST00000189978.10 linkc.1693A>C p.Met565Leu missense_variant Exon 14 of 14 5 ENSP00000189978.6 O15146-2

Frequencies

GnomAD3 genomes
AF:
0.000263
AC:
40
AN:
152030
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00123
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000368
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000310
AC:
77
AN:
248074
Hom.:
0
AF XY:
0.000268
AC XY:
36
AN XY:
134500
show subpopulations
Gnomad AFR exome
AF:
0.0000646
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00219
Gnomad NFE exome
AF:
0.000223
Gnomad OTH exome
AF:
0.000498
GnomAD4 exome
AF:
0.000202
AC:
295
AN:
1458638
Hom.:
0
Cov.:
32
AF XY:
0.000214
AC XY:
155
AN XY:
724998
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00264
Gnomad4 NFE exome
AF:
0.000130
Gnomad4 OTH exome
AF:
0.000149
GnomAD4 genome
AF:
0.000263
AC:
40
AN:
152148
Hom.:
0
Cov.:
32
AF XY:
0.000296
AC XY:
22
AN XY:
74402
show subpopulations
Gnomad4 AFR
AF:
0.0000482
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00123
Gnomad4 NFE
AF:
0.000368
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000271
Hom.:
0
Bravo
AF:
0.000125
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000237
AC:
2
ExAC
AF:
0.000239
AC:
29
EpiCase
AF:
0.000109
EpiControl
AF:
0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1
Sep 15, 2023
Revvity Omics, Revvity
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Fetal akinesia deformation sequence 1;C4225368:Congenital myasthenic syndrome 9 Benign:1
Jan 30, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.29
BayesDel_addAF
Benign
-0.30
T
BayesDel_noAF
Benign
-0.23
CADD
Benign
23
DANN
Uncertain
0.98
DEOGEN2
Benign
0.37
T;.;.;.
Eigen
Uncertain
0.23
Eigen_PC
Uncertain
0.34
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Benign
0.81
T;T;T;T
M_CAP
Benign
0.024
T
MetaRNN
Benign
0.039
T;T;T;T
MetaSVM
Benign
-0.76
T
MutationAssessor
Benign
-1.4
N;.;.;.
PrimateAI
Uncertain
0.76
T
PROVEAN
Benign
-1.9
N;.;.;.
REVEL
Benign
0.26
Sift
Benign
0.24
T;.;.;.
Sift4G
Benign
0.56
T;T;T;T
Polyphen
0.92
P;.;.;.
Vest4
0.44
MutPred
0.47
Loss of methylation at K649 (P = 0.0859);.;.;.;
MVP
0.39
MPC
0.15
ClinPred
0.98
D
GERP RS
5.1
Varity_R
0.46
gMVP
0.57

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: rs199811263; hg19: chr9-113562609; API