chr9-110695446-G-A

Position:

• chr9-110695446-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005592.4(MUSK):​c.402G>A​(p.Glu134=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.175 in 1,535,178 control chromosomes in the GnomAD database, including 24,102 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2166 hom., cov: 33)
  • Exomes 𝑓: 0.18 (21936 hom.)
• Consequence: MUSK NM_005592.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.227

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 9-110695446-G-A is Benign according to our data. Variant chr9-110695446-G-A is described in ClinVar as [Benign]. Clinvar id is 129635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-110695446-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.227 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.203 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUSK	NM_005592.4	c.402G>A	p.Glu134=	synonymous_variant	4/15	ENST00000374448.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUSK	ENST00000374448.9	c.402G>A	p.Glu134=	synonymous_variant	4/15	5	NM_005592.4	P4
MUSK	ENST00000416899.7	c.402G>A	p.Glu134=	synonymous_variant	4/14	5		A1
MUSK	ENST00000189978.10	c.402G>A	p.Glu134=	synonymous_variant	4/14	5
MUSK	ENST00000374439.1	c.96G>A	p.Glu32=	synonymous_variant	2/4	5

Frequencies

GnomAD3 genomes AF: 0.166 AC: 25184 AN: 151970 Hom.: 2163 Cov.: 33

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.0758

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.214

Gnomad SAS AF: 0.184

Gnomad FIN AF: 0.145

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.187

Gnomad OTH AF: 0.160

GnomAD3 exomes AF: 0.159 AC: 27829 AN: 175058 Hom.: 2327 AF XY: 0.163 AC XY: 15162 AN XY: 92840

Gnomad AFR exome AF: 0.131

Gnomad AMR exome AF: 0.0848

Gnomad ASJ exome AF: 0.132

Gnomad EAS exome AF: 0.212

Gnomad SAS exome AF: 0.175

Gnomad FIN exome AF: 0.157

Gnomad NFE exome AF: 0.178

Gnomad OTH exome AF: 0.164

GnomAD4 exome AF: 0.176 AC: 242898 AN: 1383090 Hom.: 21936 Cov.: 27 AF XY: 0.176 AC XY: 120764 AN XY: 684428

Gnomad4 AFR exome AF: 0.135

Gnomad4 AMR exome AF: 0.0927

Gnomad4 ASJ exome AF: 0.132

Gnomad4 EAS exome AF: 0.226

Gnomad4 SAS exome AF: 0.180

Gnomad4 FIN exome AF: 0.160

Gnomad4 NFE exome AF: 0.180

Gnomad4 OTH exome AF: 0.171

GnomAD4 genome AF: 0.166 AC: 25199 AN: 152088 Hom.: 2166 Cov.: 33 AF XY: 0.164 AC XY: 12180 AN XY: 74334

Gnomad4 AFR AF: 0.142

Gnomad4 AMR AF: 0.139

Gnomad4 ASJ AF: 0.141

Gnomad4 EAS AF: 0.214

Gnomad4 SAS AF: 0.183

Gnomad4 FIN AF: 0.145

Gnomad4 NFE AF: 0.187

Gnomad4 OTH AF: 0.161

Alfa AF: 0.174 Hom.: 1205

Bravo AF: 0.159

Asia WGS AF: 0.185 AC: 640 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 27, 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -

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
BayesDel_noAF	Benign	-0.52
CADD	Benign	4.1
DANN	Benign	0.49

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: rs10980531; hg19: chr9-113457726; COSMIC: COSV51879561;