9-110767960-C-G

Variant names:

• chr9-110767960-C-G
• rs200064775
• NM_005592.4:c.1061C>G

Variant summary

Our verdict is Uncertain significance. The variant received 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. 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
• Publications: 1 publications found

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]

MUSK Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 9

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
• fetal akinesia deformation sequence 1

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LOC107987115 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32227463).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005592.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUSK	NM_005592.4	MANE Select	c.1061C>G	p.Thr354Arg	missense	Exon 9 of 15	NP_005583.1
	MUSK	NM_001369398.1		c.-176C>G		5_prime_UTR	Exon 5 of 10	NP_001356327.1
	MUSK	NM_001166280.2		c.950+5752C>G		intron	N/A	NP_001159752.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUSK	ENST00000374448.9	TSL:5 MANE Select	c.1061C>G	p.Thr354Arg	missense	Exon 9 of 15	ENSP00000363571.4
	MUSK	ENST00000416899.7	TSL:5	c.1061C>G	p.Thr354Arg	missense	Exon 9 of 14	ENSP00000393608.3
	MUSK	ENST00000189978.10	TSL:5	c.950+5752C>G		intron	N/A	ENSP00000189978.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.32	T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		1.8
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.33
Sift	Benign	0.064	T
Sift4G	Benign	0.43	T
Polyphen		0.97	D
Vest4		0.31
MutPred		0.46		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
Mutation Taster		=75/25	polymorphism

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

Other links and lift over

dbSNP: rs200064775; hg19: chr9-113530240;