chr9-110785694-C-A

Position:

• chr9-110785694-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005592.4(MUSK):​c.1754C>A​(p.Ala585Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,449,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: MUSK NM_005592.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.57

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.935

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUSK	NM_005592.4	c.1754C>A	p.Ala585Glu	missense_variant	13/15	ENST00000374448.9	NP_005583.1
LOC107987115	XR_001746892.2			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUSK	ENST00000374448.9	c.1754C>A	p.Ala585Glu	missense_variant	13/15	5	NM_005592.4	ENSP00000363571	P4
MUSK	ENST00000416899.7	c.1730C>A	p.Ala577Glu	missense_variant	12/14	5		ENSP00000393608	A1
MUSK	ENST00000189978.10	c.1496C>A	p.Ala499Glu	missense_variant	12/14	5		ENSP00000189978
MUSK	ENST00000374438.1	n.785C>A		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000409 AC: 1 AN: 244662 Hom.: 0 AF XY: 0.00000753 AC XY: 1 AN XY: 132766

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: 0.0000337

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1449816 Hom.: 0 Cov.: 30 AF XY: 0.00000416 AC XY: 3 AN XY: 720742

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000477

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D;.;.;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Benign	1.9	M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-4.9	D;.;.;.
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0030	D;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.90
MutPred		0.76		Gain of disorder (P = 0.1011);.;.;.;
MVP		0.95
MPC		0.75
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.80
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs953823198; hg19: chr9-113547974; COSMIC: COSV99505374;