9-110708968-T-C

Variant names:

• chr9-110708968-T-C
• rs10512409
• NM_005592.4:c.628+11502T>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.628+11502T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.387 in 151,944 control chromosomes in the GnomAD database, including 11,853 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 0.39 (11853 hom., cov: 32)
• Consequence: MUSK NM_005592.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0800
• 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.436 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUSK	NM_005592.4	c.628+11502T>C		intron_variant	Intron 5 of 14	ENST00000374448.9	NP_005583.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUSK	ENST00000374448.9	c.628+11502T>C		intron_variant	Intron 5 of 14	5	NM_005592.4	ENSP00000363571.4
MUSK	ENST00000416899.7	c.628+11502T>C		intron_variant	Intron 5 of 13	5		ENSP00000393608.3
MUSK	ENST00000189978.10	c.628+11502T>C		intron_variant	Intron 5 of 13	5		ENSP00000189978.6

Frequencies

GnomAD3 genomes AF: 0.387 AC: 58721 AN: 151826 Hom.: 11847 Cov.: 32

Gnomad AFR AF: 0.335

Gnomad AMI AF: 0.484

Gnomad AMR AF: 0.327

Gnomad ASJ AF: 0.403

Gnomad EAS AF: 0.233

Gnomad SAS AF: 0.229

Gnomad FIN AF: 0.457

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.440

Gnomad OTH AF: 0.416

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

GnomAD4 genome AF: 0.387 AC: 58760 AN: 151944 Hom.: 11853 Cov.: 32 AF XY: 0.383 AC XY: 28475 AN XY: 74256

African (AFR) AF: 0.336 AC: 13900 AN: 41418

American (AMR) AF: 0.327 AC: 4982 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.403 AC: 1399 AN: 3468

East Asian (EAS) AF: 0.233 AC: 1205 AN: 5170

South Asian (SAS) AF: 0.230 AC: 1107 AN: 4818

European-Finnish (FIN) AF: 0.457 AC: 4824 AN: 10554

Middle Eastern (MID) AF: 0.412 AC: 121 AN: 294

European-Non Finnish (NFE) AF: 0.440 AC: 29901 AN: 67944

Other (OTH) AF: 0.417 AC: 881 AN: 2112

Alfa AF: 0.368 Hom.: 4270

Bravo AF: 0.375

Asia WGS AF: 0.237 AC: 823 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	5.9
DANN	Benign	0.87
PhyloP100		-0.080
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: rs10512409; hg19: chr9-113471248;