rs201014623

Positions:

• chr9-110767998-C-G
• chr9-110767998-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005592.4(MUSK):​c.1099C>G​(p.Arg367Gly) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MUSK NM_005592.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.34

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]

LOC107987115 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29888362).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUSK	NM_005592.4	c.1099C>G	p.Arg367Gly	missense_variant	9/15	ENST00000374448.9	NP_005583.1
LOC107987115	XR_001746892.2	n.258-3161G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUSK	ENST00000374448.9	c.1099C>G	p.Arg367Gly	missense_variant	9/15	5	NM_005592.4	ENSP00000363571	P4
MUSK	ENST00000416899.7	c.1099C>G	p.Arg367Gly	missense_variant	9/14	5		ENSP00000393608	A1
MUSK	ENST00000189978.10	c.950+5790C>G		intron_variant		5		ENSP00000189978
MUSK	ENST00000634612.1	n.521C>G		non_coding_transcript_exon_variant	6/6	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 12, 2019

This sequence change replaces arginine with glycine at codon 367 of the MUSK protein (p.Arg367Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MUSK-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.34	T;.
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.57
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-3.8	D;.
REVEL	Uncertain	0.42
Sift	Uncertain	0.0070	D;.
Sift4G	Benign	0.16	T;T
Polyphen		0.025	B;.
Vest4		0.31
MutPred		0.73		Loss of methylation at R367 (P = 0.0899);Loss of methylation at R367 (P = 0.0899);
MVP		0.64
MPC		0.37
ClinPred		0.75	D
GERP RS		3.3
Varity_R		0.29
gMVP		0.77

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: rs201014623; hg19: chr9-113530278;