rs56130155

chr9-110687135-C-T

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.225C>T(p.Tyr75=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00396 in 1,613,314 control chromosomes in the GnomAD database, including 256 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (132 hom., cov: 31)
  • Exomes 𝑓: 0.0022 (124 hom.)
• Consequence: MUSK NM_005592.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.28

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=-0.47).
• BP6: Variant 9-110687135-C-T is Benign according to our data. Variant chr9-110687135-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 129632.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-110687135-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.28 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0723 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUSK	NM_005592.4	c.225C>T	p.Tyr75=	synonymous_variant	3/15	ENST00000374448.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUSK	ENST00000374448.9	c.225C>T	p.Tyr75=	synonymous_variant	3/15	5	NM_005592.4	P4
MUSK	ENST00000416899.7	c.225C>T	p.Tyr75=	synonymous_variant	3/14	5		A1
MUSK	ENST00000189978.10	c.225C>T	p.Tyr75=	synonymous_variant	3/14	5

Frequencies

GnomAD3 genomes AF: 0.0211 AC: 3207 AN: 151952 Hom.: 130 Cov.: 31

Gnomad AFR AF: 0.0744

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00590

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.00524 AC: 1303 AN: 248758 Hom.: 55 AF XY: 0.00385 AC XY: 519 AN XY: 134902

Gnomad AFR exome AF: 0.0763

Gnomad AMR exome AF: 0.00276

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.00315

GnomAD4 exome AF: 0.00217 AC: 3167 AN: 1461242 Hom.: 124 Cov.: 31 AF XY: 0.00186 AC XY: 1349 AN XY: 726898

Gnomad4 AFR exome AF: 0.0784

Gnomad4 AMR exome AF: 0.00367

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000244

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000351

Gnomad4 OTH exome AF: 0.00499

GnomAD4 genome AF: 0.0212 AC: 3219 AN: 152072 Hom.: 132 Cov.: 31 AF XY: 0.0202 AC XY: 1505 AN XY: 74372

Gnomad4 AFR AF: 0.0745

Gnomad4 AMR AF: 0.00589

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.00973 Hom.: 34

Bravo AF: 0.0246

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 2017	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	Athena Diagnostics	Aug 19, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Congenital myasthenic syndrome 9 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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	-0.47
Cadd	Benign	9.2
Dann	Benign	0.55

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: rs56130155; hg19: chr9-113449415;