rs375762569

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PM1PM2BP4_StrongBP6BS1

The NM_005592.4(MUSK):c.1025C>T(p.Ala342Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000973 in 1,613,916 control chromosomes in the GnomAD database, including 1 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A342T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00042 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000064 ( 1 hom. )

Consequence

MUSK
NM_005592.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 1.12

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]

MUSK links:

LOC107987115 (HGNC:):

LOC107987115 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_005592.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.013663888).

BP6

Variant 9-110767924-C-T is Benign according to our data. Variant chr9-110767924-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 476129.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00042 (64/152214) while in subpopulation AFR AF= 0.00132 (55/41532). AF 95% confidence interval is 0.00104. There are 0 homozygotes in gnomad4. There are 23 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUSK	NM_005592.4 linkuse as main transcript	c.1025C>T	p.Ala342Val	missense_variant	9/15	ENST00000374448.9
LOC107987115	XR_001746892.2 linkuse as main transcript	n.258-3087G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUSK	ENST00000374448.9 linkuse as main transcript	c.1025C>T	p.Ala342Val	missense_variant	9/15	5	NM_005592.4	P4	O15146-1
MUSK	ENST00000416899.7 linkuse as main transcript	c.1025C>T	p.Ala342Val	missense_variant	9/14	5		A1
MUSK	ENST00000189978.10 linkuse as main transcript	c.950+5716C>T		intron_variant		5			O15146-2
MUSK	ENST00000634612.1 linkuse as main transcript	n.447C>T		non_coding_transcript_exon_variant	6/6	5

Frequencies

GnomAD3 genomes

AF:

0.000421

AC:

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00133

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000124

AC:

AN:

249284

Hom.:

AF XY:

0.0000961

AC XY:

AN XY:

135242

show subpopulations

Gnomad AFR exome

AF:

0.00149

Gnomad AMR exome

AF:

0.0000869

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000636

AC:

AN:

1461702

Hom.:

Cov.:

AF XY:

0.0000536

AC XY:

AN XY:

727138

show subpopulations

Gnomad4 AFR exome

AF:

0.00119

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000405

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000420

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.00132

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000263

Hom.:

Bravo

AF:

0.000484

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000124

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 25, 2022

The c.1025C>T (p.A342V) alteration is located in exon 9 (coding exon 9) of the MUSK gene. This alteration results from a C to T substitution at nucleotide position 1025, causing the alanine (A) at amino acid position 342 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jan 14, 2019

- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.52

Cadd

Benign

Dann

Benign

0.96

DEOGEN2

Benign

0.095

T;.

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.63

T;T

M_CAP

Benign

0.020

MetaRNN

Benign

0.014

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.92

L;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.34

N;.

REVEL

Benign

0.081

Sift

Benign

0.26

T;.

Sift4G

Benign

0.28

T;T

Polyphen

0.21

B;.

Vest4

0.14

MVP

0.56

MPC

0.16

ClinPred

0.012

GERP RS

-0.79

Varity_R

0.032

gMVP

0.59

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