rs35142681

Variant names:

• chr9-110687209-C-T
• rs35142681
• NM_005592.4:c.299C>T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005592.4(MUSK):​c.299C>T​(p.Thr100Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0269 in 1,613,722 control chromosomes in the GnomAD database, including 711 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (44 hom., cov: 31)
  • Exomes 𝑓: 0.027 (667 hom.)
• Consequence: MUSK NM_005592.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.213

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 -18 ACMG points.

• PM1: In a domain Ig-like 1 (size 88) in uniprot entity MUSK_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_005592.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0064065754).
• BP6: Variant 9-110687209-C-T is Benign according to our data. Variant chr9-110687209-C-T is described in ClinVar as [Benign]. Clinvar id is 129634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-110687209-C-T is described in Lovd as [Benign]. Variant chr9-110687209-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0213 (3236/152218) while in subpopulation NFE AF= 0.0324 (2206/68016). AF 95% confidence interval is 0.0313. There are 44 homozygotes in gnomad4. There are 1504 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 44 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUSK	NM_005592.4	c.299C>T	p.Thr100Met	missense_variant	Exon 3 of 15	ENST00000374448.9	NP_005583.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUSK	ENST00000374448.9	c.299C>T	p.Thr100Met	missense_variant	Exon 3 of 15	5	NM_005592.4	ENSP00000363571.4
MUSK	ENST00000416899.7	c.299C>T	p.Thr100Met	missense_variant	Exon 3 of 14	5		ENSP00000393608.3
MUSK	ENST00000189978.10	c.299C>T	p.Thr100Met	missense_variant	Exon 3 of 14	5		ENSP00000189978.6
MUSK	ENST00000374439.1	c.-8C>T		upstream_gene_variant		5		ENSP00000363562.2

Frequencies

GnomAD3 genomes AF: 0.0213 AC: 3236 AN: 152100 Hom.: 44 Cov.: 31

Gnomad AFR AF: 0.00625

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0191

Gnomad ASJ AF: 0.0259

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.0290

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0324

Gnomad OTH AF: 0.0196

GnomAD3 exomes AF: 0.0230 AC: 5741 AN: 249182 Hom.: 107 AF XY: 0.0230 AC XY: 3108 AN XY: 135186

Gnomad AFR exome AF: 0.00568

Gnomad AMR exome AF: 0.0123

Gnomad ASJ exome AF: 0.0276

Gnomad EAS exome AF: 0.00362

Gnomad SAS exome AF: 0.00451

Gnomad FIN exome AF: 0.0310

Gnomad NFE exome AF: 0.0348

Gnomad OTH exome AF: 0.0246

GnomAD4 exome AF: 0.0274 AC: 40103 AN: 1461504 Hom.: 667 Cov.: 31 AF XY: 0.0269 AC XY: 19524 AN XY: 727020

Gnomad4 AFR exome AF: 0.00463

Gnomad4 AMR exome AF: 0.0125

Gnomad4 ASJ exome AF: 0.0253

Gnomad4 EAS exome AF: 0.00146

Gnomad4 SAS exome AF: 0.00450

Gnomad4 FIN exome AF: 0.0309

Gnomad4 NFE exome AF: 0.0315

Gnomad4 OTH exome AF: 0.0252

GnomAD4 genome AF: 0.0213 AC: 3236 AN: 152218 Hom.: 44 Cov.: 31 AF XY: 0.0202 AC XY: 1504 AN XY: 74412

Gnomad4 AFR AF: 0.00623

Gnomad4 AMR AF: 0.0190

Gnomad4 ASJ AF: 0.0259

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.0290

Gnomad4 NFE AF: 0.0324

Gnomad4 OTH AF: 0.0199

Alfa AF: 0.0289 Hom.: 128

Bravo AF: 0.0204

TwinsUK AF: 0.0286 AC: 106

ALSPAC AF: 0.0322 AC: 124

ESP6500AA AF: 0.00714 AC: 29

ESP6500EA AF: 0.0302 AC: 254

ExAC AF: 0.0238 AC: 2880

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 13, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 05, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital myasthenic syndrome 9 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	Benign	0.11
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	12
DANN	Benign	0.85
DEOGEN2	Benign	0.13	T;.;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.026	N
LIST_S2	Uncertain	0.91	D;D;D;D
MetaRNN	Benign	0.0064	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L;.;L;.
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.11	N;N;N;.
REVEL	Benign	0.11
Sift	Benign	0.23	T;T;T;.
Sift4G	Benign	0.12	T;T;T;T
Polyphen		0.16	B;.;.;.
Vest4		0.092
MPC		0.19
ClinPred		0.0073	T
GERP RS		-7.1
Varity_R		0.039
gMVP		0.46

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: rs35142681; hg19: chr9-113449489; COSMIC: COSV105049818; COSMIC: COSV105049818;