rs41279055

Positions:

• chr9-110800309-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_005592.4(MUSK):​c.1931T>C​(p.Val644Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00357 in 1,604,290 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V644L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0027 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (15 hom.)
• Consequence: MUSK NM_005592.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:6
• Conservation: PhyloP100: 7.95

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.057576776).
• BP6: Variant 9-110800309-T-C is Benign according to our data. Variant chr9-110800309-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 259805.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=6}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00266 (404/151880) while in subpopulation SAS AF= 0.00461 (22/4772). AF 95% confidence interval is 0.00363. There are 3 homozygotes in gnomad4. There are 216 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUSK	NM_005592.4	c.1931T>C	p.Val644Ala	missense_variant	15/15	ENST00000374448.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUSK	ENST00000374448.9	c.1931T>C	p.Val644Ala	missense_variant	15/15	5	NM_005592.4	P4
MUSK	ENST00000416899.7	c.1907T>C	p.Val636Ala	missense_variant	14/14	5		A1
MUSK	ENST00000189978.10	c.1673T>C	p.Val558Ala	missense_variant	14/14	5

Frequencies

GnomAD3 genomes AF: 0.00266 AC: 404 AN: 151762 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000388

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00461

Gnomad FIN AF: 0.00274

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00402

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.00298 AC: 730 AN: 245278 Hom.: 4 AF XY: 0.00322 AC XY: 428 AN XY: 132922

Gnomad AFR exome AF: 0.000259

Gnomad AMR exome AF: 0.00158

Gnomad ASJ exome AF: 0.00145

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.00368

Gnomad FIN exome AF: 0.00269

Gnomad NFE exome AF: 0.00427

Gnomad OTH exome AF: 0.00268

GnomAD4 exome AF: 0.00367 AC: 5329 AN: 1452410 Hom.: 15 Cov.: 32 AF XY: 0.00364 AC XY: 2627 AN XY: 720868

Gnomad4 AFR exome AF: 0.000330

Gnomad4 AMR exome AF: 0.00182

Gnomad4 ASJ exome AF: 0.00160

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00351

Gnomad4 FIN exome AF: 0.00258

Gnomad4 NFE exome AF: 0.00411

Gnomad4 OTH exome AF: 0.00319

GnomAD4 genome AF: 0.00266 AC: 404 AN: 151880 Hom.: 3 Cov.: 32 AF XY: 0.00291 AC XY: 216 AN XY: 74248

Gnomad4 AFR AF: 0.000386

Gnomad4 AMR AF: 0.00321

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00461

Gnomad4 FIN AF: 0.00274

Gnomad4 NFE AF: 0.00402

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00322 Hom.: 0

Bravo AF: 0.00284

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000481 AC: 2

ESP6500EA AF: 0.00344 AC: 29

ExAC AF: 0.00273 AC: 330

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Mar 22, 2021	BS1 -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	MUSK: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 03, 2017	- -

not specified Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 25, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 08, 2016	- -

Congenital myasthenic syndrome 9 Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Benign	0.0069	T
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;.;.;.
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.77	T;T;T;T
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.058	T;T;T;T
MetaSVM	Uncertain	-0.068	T
MutationAssessor	Benign	1.4	L;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.7	D;.;.;.
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0020	D;.;.;.
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		0.37	B;.;.;.
Vest4		0.87
MVP		0.85
MPC		0.76
ClinPred		0.036	T
GERP RS		5.1
Varity_R		0.58
gMVP		0.69

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: rs41279055; hg19: chr9-113562589; COSMIC: COSV105851562;