rs200064775

Positions:

• chr9-110767960-C-G
• chr9-110767960-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.1061C>G​(p.Thr354Arg) 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. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T354M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MUSK NM_005592.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.82

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=0.32227463).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUSK	NM_005592.4	c.1061C>G	p.Thr354Arg	missense_variant	9/15	ENST00000374448.9
LOC107987115	XR_001746892.2	n.258-3123G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUSK	ENST00000374448.9	c.1061C>G	p.Thr354Arg	missense_variant	9/15	5	NM_005592.4	P4
MUSK	ENST00000416899.7	c.1061C>G	p.Thr354Arg	missense_variant	9/14	5		A1
MUSK	ENST00000189978.10	c.950+5752C>G		intron_variant		5
MUSK	ENST00000634612.1	n.483C>G		non_coding_transcript_exon_variant	6/6	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T;.
Eigen	Benign	0.12
Eigen_PC	Benign	0.024
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.32	T;T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Uncertain	2.0	M;.
MutationTaster	Benign	0.93	N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.1	N;.
REVEL	Uncertain	0.33
Sift	Benign	0.064	T;.
Sift4G	Benign	0.43	T;T
Polyphen		0.97	D;.
Vest4		0.31
MutPred		0.46		Gain of disorder (P = 0.2369);Gain of disorder (P = 0.2369);
MVP		0.86
MPC		0.62
ClinPred		0.87	D
GERP RS		3.2
Varity_R		0.12
gMVP		0.79

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: rs200064775; hg19: chr9-113530240;