9-110721711-G-C

Variant names:

• chr9-110721711-G-C
• rs10733579
• NM_005592.4:c.629-12540G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005592.4(MUSK):​c.629-12540G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.703 in 152,000 control chromosomes in the GnomAD database, including 37,918 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.70 (37918 hom., cov: 31)
• Consequence: MUSK NM_005592.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.85
• Publications: 3 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)
• fetal akinesia deformation sequence 1

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.09).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.83 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUSK	NM_005592.4	MANE Select	c.629-12540G>C		intron	N/A	NP_005583.1	O15146-1
	MUSK	NM_001166280.2		c.629-6977G>C		intron	N/A	NP_001159752.1	O15146-2
	MUSK	NM_001166281.2		c.629-12540G>C		intron	N/A	NP_001159753.1	O15146-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUSK	ENST00000374448.9	TSL:5 MANE Select	c.629-12540G>C		intron	N/A	ENSP00000363571.4	O15146-1
	MUSK	ENST00000416899.7	TSL:5	c.629-12540G>C		intron	N/A	ENSP00000393608.3	A0A087WSY1
	MUSK	ENST00000189978.10	TSL:5	c.629-6977G>C		intron	N/A	ENSP00000189978.6	O15146-2

Frequencies

GnomAD3 genomes AF: 0.703 AC: 106799 AN: 151882 Hom.: 37901 Cov.: 31

Gnomad AFR AF: 0.739

Gnomad AMI AF: 0.667

Gnomad AMR AF: 0.659

Gnomad ASJ AF: 0.781

Gnomad EAS AF: 0.851

Gnomad SAS AF: 0.629

Gnomad FIN AF: 0.624

Gnomad MID AF: 0.785

Gnomad NFE AF: 0.692

Gnomad OTH AF: 0.751

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.703 AC: 106872 AN: 152000 Hom.: 37918 Cov.: 31 AF XY: 0.700 AC XY: 52019 AN XY: 74306

African (AFR) AF: 0.739 AC: 30654 AN: 41480

American (AMR) AF: 0.659 AC: 10059 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.781 AC: 2710 AN: 3468

East Asian (EAS) AF: 0.851 AC: 4389 AN: 5156

South Asian (SAS) AF: 0.629 AC: 3028 AN: 4816

European-Finnish (FIN) AF: 0.624 AC: 6597 AN: 10566

Middle Eastern (MID) AF: 0.789 AC: 232 AN: 294

European-Non Finnish (NFE) AF: 0.692 AC: 47003 AN: 67934

Other (OTH) AF: 0.752 AC: 1592 AN: 2116

Alfa AF: 0.606 Hom.: 1701

Bravo AF: 0.706

Asia WGS AF: 0.704 AC: 2450 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.36
DANN	Benign	0.34
PhyloP100		-1.9
Mutation Taster		=100/0	polymorphism (auto)

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: rs10733579; hg19: chr9-113483991;