rs55980069

Positions:

• chr9-110695442-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005592.4(MUSK):​c.398T>C​(p.Ile133Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00592 in 1,539,768 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I133V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0061 (38 hom.)
• Consequence: MUSK NM_005592.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.74

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006833166).
• BP6: Variant 9-110695442-T-C is Benign according to our data. Variant chr9-110695442-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 197256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-110695442-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00393 (599/152300) while in subpopulation NFE AF= 0.0061 (415/68006). AF 95% confidence interval is 0.00562. There are 0 homozygotes in gnomad4. There are 298 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 38 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUSK	NM_005592.4	c.398T>C	p.Ile133Thr	missense_variant	4/15	ENST00000374448.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUSK	ENST00000374448.9	c.398T>C	p.Ile133Thr	missense_variant	4/15	5	NM_005592.4	P4
MUSK	ENST00000416899.7	c.398T>C	p.Ile133Thr	missense_variant	4/14	5		A1
MUSK	ENST00000189978.10	c.398T>C	p.Ile133Thr	missense_variant	4/14	5
MUSK	ENST00000374439.1	c.92T>C	p.Ile31Thr	missense_variant	2/4	5

Frequencies

GnomAD3 genomes AF: 0.00394 AC: 599 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00610

Gnomad OTH AF: 0.00764

GnomAD3 exomes AF: 0.00451 AC: 796 AN: 176308 Hom.: 8 AF XY: 0.00443 AC XY: 414 AN XY: 93462

Gnomad AFR exome AF: 0.00132

Gnomad AMR exome AF: 0.00260

Gnomad ASJ exome AF: 0.0109

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00278

Gnomad FIN exome AF: 0.00209

Gnomad NFE exome AF: 0.00673

Gnomad OTH exome AF: 0.00553

GnomAD4 exome AF: 0.00613 AC: 8511 AN: 1387468 Hom.: 38 Cov.: 27 AF XY: 0.00600 AC XY: 4122 AN XY: 686668

Gnomad4 AFR exome AF: 0.00104

Gnomad4 AMR exome AF: 0.00321

Gnomad4 ASJ exome AF: 0.0110

Gnomad4 EAS exome AF: 0.0000267

Gnomad4 SAS exome AF: 0.00299

Gnomad4 FIN exome AF: 0.00207

Gnomad4 NFE exome AF: 0.00694

Gnomad4 OTH exome AF: 0.00578

GnomAD4 genome AF: 0.00393 AC: 599 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.00400 AC XY: 298 AN XY: 74482

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.0112

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00245

Gnomad4 NFE AF: 0.00610

Gnomad4 OTH AF: 0.00756

Alfa AF: 0.00589 Hom.: 5

Bravo AF: 0.00403

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.00110 AC: 4

ESP6500EA AF: 0.00690 AC: 56

ExAC AF: 0.00323 AC: 384

Asia WGS AF: 0.00115 AC: 5 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 05, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 13, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	MUSK: BS2 -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 17, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 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. -

MUSK-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 29, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	20
DANN	Benign	0.91
DEOGEN2	Benign	0.13	T;.;.;.;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.86	D;D;D;D;D
MetaRNN	Benign	0.0068	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.53	N;.;N;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.0	N;N;N;.;.
REVEL	Benign	0.042
Sift	Benign	0.061	T;T;T;.;.
Sift4G	Benign	0.62	T;T;T;T;T
Polyphen		0.0060	B;.;.;.;.
Vest4		0.35
MVP		0.36
MPC		0.21
ClinPred		0.019	T
GERP RS		1.2
Varity_R		0.071
gMVP		0.67

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: rs55980069; hg19: chr9-113457722;