rs200750233

chr9-110695530-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005592.4(MUSK):c.486G>C(p.Arg162Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000203 in 1,549,130 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R162R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: MUSK NM_005592.4 missense, splice_region
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 4.73

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUSK	NM_005592.4	c.486G>C	p.Arg162Ser	missense_variant, splice_region_variant	4/15	ENST00000374448.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUSK	ENST00000374448.9	c.486G>C	p.Arg162Ser	missense_variant, splice_region_variant	4/15	5	NM_005592.4	P4
MUSK	ENST00000416899.7	c.486G>C	p.Arg162Ser	missense_variant, splice_region_variant	4/14	5		A1
MUSK	ENST00000189978.10	c.486G>C	p.Arg162Ser	missense_variant, splice_region_variant	4/14	5
MUSK	ENST00000374439.1	c.180G>C	p.Arg60Ser	missense_variant, splice_region_variant	2/4	5

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152042 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000287 AC: 48 AN: 167072 Hom.: 0 AF XY: 0.000283 AC XY: 25 AN XY: 88294

Gnomad AFR exome AF: 0.000206

Gnomad AMR exome AF: 0.000504

Gnomad ASJ exome AF: 0.00211

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000228

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000193 AC: 270 AN: 1396970 Hom.: 0 Cov.: 28 AF XY: 0.000207 AC XY: 143 AN XY: 689872

Gnomad4 AFR exome AF: 0.000285

Gnomad4 AMR exome AF: 0.000397

Gnomad4 ASJ exome AF: 0.00299

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000128

Gnomad4 OTH exome AF: 0.000413

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152160 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74402

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000177

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000309 Hom.: 0

Bravo AF: 0.000344

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000276 AC: 1

ESP6500EA AF: 0.000247 AC: 2

ExAC AF: 0.000188 AC: 22

Asia WGS AF: 0.000578 AC: 2 AN: 3472

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital myasthenic syndrome 9 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 25, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 09, 2015

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.22
Cadd	Uncertain	26
Dann	Uncertain	0.99
DEOGEN2	Benign	0.10	T;.;.;.;.
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;D;D;D;T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.050	T;T;T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.46	N;.;N;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.84	N;N;N;.;.
REVEL	Benign	0.18
Sift	Benign	0.064	T;T;D;.;.
Sift4G	Uncertain	0.033	D;T;T;T;T
Polyphen		0.42	B;.;.;.;.
Vest4		0.43
MutPred		0.56		Gain of disorder (P = 0.07);Gain of disorder (P = 0.07);Gain of disorder (P = 0.07);Gain of disorder (P = 0.07);.;
MVP		0.75
MPC		0.23
ClinPred		0.021	T
GERP RS		6.0
Varity_R		0.27
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.010		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: rs200750233; hg19: chr9-113457810;