rs1554732832

Positions:

• chr9-110682749-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_005592.4(MUSK):​c.155A>C​(p.Glu52Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MUSK NM_005592.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.56

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.

• 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
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUSK	NM_005592.4	c.155A>C	p.Glu52Ala	missense_variant	2/15	ENST00000374448.9	NP_005583.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUSK	ENST00000374448.9	c.155A>C	p.Glu52Ala	missense_variant	2/15	5	NM_005592.4	ENSP00000363571.4
MUSK	ENST00000416899.7	c.155A>C	p.Glu52Ala	missense_variant	2/14	5		ENSP00000393608.3
MUSK	ENST00000189978.10	c.155A>C	p.Glu52Ala	missense_variant	2/14	5		ENSP00000189978.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 11, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;.;.;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Benign	0.054	D
MetaRNN	Uncertain	0.44	T;T;T;T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	1.0	L;.;L;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.6	N;N;N;.
REVEL	Uncertain	0.35
Sift	Uncertain	0.0070	D;D;D;.
Sift4G	Benign	0.091	T;T;T;T
Polyphen		0.65	P;.;.;.
Vest4		0.43
MutPred		0.44		Gain of glycosylation at S53 (P = 0.1155);Gain of glycosylation at S53 (P = 0.1155);Gain of glycosylation at S53 (P = 0.1155);Gain of glycosylation at S53 (P = 0.1155);
MVP		0.77
MPC		0.50
ClinPred		0.95	D
GERP RS		5.5
Varity_R		0.24
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: rs1554732832; hg19: chr9-113445029;