rs2274419

chr9-110775842-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005592.4(MUSK):c.1239G>A(p.Met413Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 1,613,518 control chromosomes in the GnomAD database, including 14,411 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M413T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.099 (963 hom., cov: 32)
  • Exomes 𝑓: 0.13 (13448 hom.)
• Consequence: MUSK NM_005592.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.872

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]

LOC107987115 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0040370524).
• BP6: Variant 9-110775842-G-A is Benign according to our data. Variant chr9-110775842-G-A is described in ClinVar as [Benign]. Clinvar id is 129630.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-110775842-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.191 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUSK	NM_005592.4	c.1239G>A	p.Met413Ile	missense_variant	10/15	ENST00000374448.9
LOC107987115	XR_001746892.2	n.257+8971C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUSK	ENST00000374448.9	c.1239G>A	p.Met413Ile	missense_variant	10/15	5	NM_005592.4	P4
MUSK	ENST00000416899.7	c.1239G>A	p.Met413Ile	missense_variant	10/14	5		A1
MUSK	ENST00000189978.10	c.1005G>A	p.Met335Ile	missense_variant	10/14	5
MUSK	ENST00000374438.1	n.496G>A		non_coding_transcript_exon_variant	1/3	3

Frequencies

GnomAD3 genomes AF: 0.0988 AC: 15021 AN: 151960 Hom.: 964 Cov.: 32

Gnomad AFR AF: 0.0223

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.0551

Gnomad ASJ AF: 0.103

Gnomad EAS AF: 0.201

Gnomad SAS AF: 0.147

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.0705

GnomAD3 exomes AF: 0.120 AC: 29807 AN: 249200 Hom.: 2125 AF XY: 0.124 AC XY: 16754 AN XY: 135196

Gnomad AFR exome AF: 0.0197

Gnomad AMR exome AF: 0.0403

Gnomad ASJ exome AF: 0.0978

Gnomad EAS exome AF: 0.196

Gnomad SAS exome AF: 0.150

Gnomad FIN exome AF: 0.158

Gnomad NFE exome AF: 0.133

Gnomad OTH exome AF: 0.107

GnomAD4 exome AF: 0.132 AC: 192302 AN: 1461440 Hom.: 13448 Cov.: 32 AF XY: 0.133 AC XY: 96646 AN XY: 727022

Gnomad4 AFR exome AF: 0.0172

Gnomad4 AMR exome AF: 0.0413

Gnomad4 ASJ exome AF: 0.100

Gnomad4 EAS exome AF: 0.224

Gnomad4 SAS exome AF: 0.148

Gnomad4 FIN exome AF: 0.158

Gnomad4 NFE exome AF: 0.135

Gnomad4 OTH exome AF: 0.111

GnomAD4 genome AF: 0.0988 AC: 15020 AN: 152078 Hom.: 963 Cov.: 32 AF XY: 0.100 AC XY: 7443 AN XY: 74350

Gnomad4 AFR AF: 0.0223

Gnomad4 AMR AF: 0.0550

Gnomad4 ASJ AF: 0.103

Gnomad4 EAS AF: 0.201

Gnomad4 SAS AF: 0.148

Gnomad4 FIN AF: 0.156

Gnomad4 NFE AF: 0.135

Gnomad4 OTH AF: 0.0707

Alfa AF: 0.120 Hom.: 2038

Bravo AF: 0.0861

TwinsUK AF: 0.135 AC: 501

ALSPAC AF: 0.137 AC: 527

ESP6500AA AF: 0.0219 AC: 83

ESP6500EA AF: 0.133 AC: 1094

ExAC AF: 0.121 AC: 14602

Asia WGS AF: 0.162 AC: 562 AN: 3478

EpiCase AF: 0.127

EpiControl AF: 0.120

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2016	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. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Congenital myasthenic syndrome 9 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This 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	Pathogenic	0.62
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	16
Dann	Benign	0.91
DEOGEN2	Benign	0.075	T;.;.;.
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.47
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.85	T;T;D;D
MetaRNN	Benign	0.0040	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.88	L;.;.;.
MutationTaster	Benign	0.17	P;P;P;P
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.18	N;.;.;.
REVEL	Benign	0.063
Sift	Benign	0.60	T;.;.;.
Sift4G	Benign	0.50	T;T;T;T
Polyphen		0.0	B;.;.;.
Vest4		0.048
MutPred		0.48		Gain of methylation at K416 (P = 0.0832);Gain of methylation at K416 (P = 0.0832);.;.;
MPC		0.18
ClinPred		0.0050	T
GERP RS		1.1
Varity_R		0.052
gMVP		0.23

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

Other links and lift over

dbSNP: rs2274419; hg19: chr9-113538122; COSMIC: COSV51886200;