9-110785707-G-A

Variant names:

• chr9-110785707-G-A
• rs546916589
• NM_005592.4:c.1767G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_005592.4(MUSK):​c.1767G>A​(p.Val589Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,446,204 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. V589V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MUSK NM_005592.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0910
• Publications: 0 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP7: Synonymous conserved (PhyloP=-0.091 with no splicing effect.

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.1767G>A	p.Val589Val	synonymous	Exon 13 of 15	NP_005583.1
	MUSK	NM_001166280.2		c.1509G>A	p.Val503Val	synonymous	Exon 12 of 14	NP_001159752.1
	MUSK	NM_001166281.2		c.1479G>A	p.Val493Val	synonymous	Exon 11 of 13	NP_001159753.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUSK	ENST00000374448.9	TSL:5 MANE Select	c.1767G>A	p.Val589Val	synonymous	Exon 13 of 15	ENSP00000363571.4
	MUSK	ENST00000416899.7	TSL:5	c.1743G>A	p.Val581Val	synonymous	Exon 12 of 14	ENSP00000393608.3
	MUSK	ENST00000189978.10	TSL:5	c.1509G>A	p.Val503Val	synonymous	Exon 12 of 14	ENSP00000189978.6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1446204 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 718484

African (AFR) AF: 0.00 AC: 0 AN: 33144

American (AMR) AF: 0.00 AC: 0 AN: 43676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25736

East Asian (EAS) AF: 0.00 AC: 0 AN: 39360

South Asian (SAS) AF: 0.00 AC: 0 AN: 82768

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52938

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 9.06e-7 AC: 1 AN: 1103148

Other (OTH) AF: 0.00 AC: 0 AN: 59720

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	7.6
DANN	Benign	0.70
PhyloP100		-0.091

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

Other links and lift over

dbSNP: rs546916589; hg19: chr9-113547987;