rs35176182

Positions:

• chr9-110695519-A-C
• chr9-110695519-A-G
• chr9-110695519-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005592.4(MUSK):​c.475A>C​(p.Ser159Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MUSK NM_005592.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.62

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09216654).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUSK	NM_005592.4	c.475A>C	p.Ser159Arg	missense_variant	4/15	ENST00000374448.9	NP_005583.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUSK	ENST00000374448.9	c.475A>C	p.Ser159Arg	missense_variant	4/15	5	NM_005592.4	ENSP00000363571	P4
MUSK	ENST00000416899.7	c.475A>C	p.Ser159Arg	missense_variant	4/14	5		ENSP00000393608	A1
MUSK	ENST00000189978.10	c.475A>C	p.Ser159Arg	missense_variant	4/14	5		ENSP00000189978
MUSK	ENST00000374439.1	c.169A>C	p.Ser57Arg	missense_variant	2/4	5		ENSP00000363562

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000561 AC: 1 AN: 178208 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 94378

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000133

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000853 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Benign	0.094	T;.;.;.;.
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.83	T;T;T;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.092	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.37	N;.;N;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.95	N;N;N;.;.
REVEL	Benign	0.051
Sift	Benign	0.50	T;T;T;.;.
Sift4G	Benign	0.52	T;T;T;T;T
Polyphen		0.0020	B;.;.;.;.
Vest4		0.20
MutPred		0.49		Gain of MoRF binding (P = 0.0128);Gain of MoRF binding (P = 0.0128);Gain of MoRF binding (P = 0.0128);Gain of MoRF binding (P = 0.0128);.;
MVP		0.62
MPC		0.18
ClinPred		0.037	T
GERP RS		3.4
Varity_R		0.19
gMVP		0.34

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: rs35176182; hg19: chr9-113457799;