rs756953369

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_005592.4(MUSK):​c.635C>T​(p.Ala212Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000343 in 1,459,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

MUSK
NM_005592.4 missense

Scores

5
4
10

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.76
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 Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.794

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MUSKNM_005592.4 linkuse as main transcriptc.635C>T p.Ala212Val missense_variant 6/15 ENST00000374448.9 NP_005583.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MUSKENST00000374448.9 linkuse as main transcriptc.635C>T p.Ala212Val missense_variant 6/155 NM_005592.4 ENSP00000363571 P4O15146-1
MUSKENST00000416899.7 linkuse as main transcriptc.635C>T p.Ala212Val missense_variant 6/145 ENSP00000393608 A1
MUSKENST00000189978.10 linkuse as main transcriptc.665C>T p.Ala222Val missense_variant 7/145 ENSP00000189978 O15146-2
MUSKENST00000634612.1 linkuse as main transcriptn.57C>T non_coding_transcript_exon_variant 3/65

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000122
AC:
3
AN:
245106
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
132972
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000588
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000902
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000343
AC:
5
AN:
1459032
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
725614
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000451
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000508
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.00000828
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 22, 2024The c.635C>T (p.A212V) alteration is located in exon 6 (coding exon 6) of the MUSK gene. This alteration results from a C to T substitution at nucleotide position 635, causing the alanine (A) at amino acid position 212 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Fetal akinesia deformation sequence 1;C4225368:Congenital myasthenic syndrome 9 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 28, 2021This sequence change replaces alanine with valine at codon 212 of the MUSK protein (p.Ala212Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs756953369, ExAC 0.01%). This variant has not been reported in the literature in individuals affected with MUSK-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.68
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Benign
-0.25
CADD
Pathogenic
28
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.14
T;.;.;.
Eigen
Pathogenic
0.75
Eigen_PC
Pathogenic
0.71
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Uncertain
0.97
D;D;D;D
M_CAP
Benign
0.027
D
MetaRNN
Pathogenic
0.79
D;D;D;D
MetaSVM
Benign
-0.79
T
MutationAssessor
Uncertain
2.4
M;.;.;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.67
T
PROVEAN
Benign
-0.77
N;N;.;.
REVEL
Benign
0.26
Sift
Benign
0.12
T;T;.;.
Sift4G
Benign
0.13
T;T;T;T
Polyphen
1.0
D;.;.;.
Vest4
0.80
MutPred
0.70
Gain of MoRF binding (P = 0.2147);Gain of MoRF binding (P = 0.2147);.;.;
MVP
0.50
MPC
0.69
ClinPred
0.88
D
GERP RS
5.2
Varity_R
0.23
gMVP
0.69

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.090
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: rs756953369; hg19: chr9-113496537; API