NM_005592.4:c.628+14420G>C

Variant names:

• chr9-110711886-G-C
• rs10817082
• NM_005592.4:c.628+14420G>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+14420G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.566 in 152,044 control chromosomes in the GnomAD database, including 25,381 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 0.57 (25381 hom., cov: 32)
• Consequence: MUSK NM_005592.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.79
• Publications: 2 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=-1.03).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.635 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUSK	NM_005592.4	MANE Select	c.628+14420G>C		intron	N/A	NP_005583.1
	MUSK	NM_001166280.2		c.628+14420G>C		intron	N/A	NP_001159752.1
	MUSK	NM_001166281.2		c.628+14420G>C		intron	N/A	NP_001159753.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUSK	ENST00000374448.9	TSL:5 MANE Select	c.628+14420G>C		intron	N/A	ENSP00000363571.4
	MUSK	ENST00000416899.7	TSL:5	c.628+14420G>C		intron	N/A	ENSP00000393608.3
	MUSK	ENST00000189978.10	TSL:5	c.628+14420G>C		intron	N/A	ENSP00000189978.6

Frequencies

GnomAD3 genomes AF: 0.566 AC: 86001 AN: 151926 Hom.: 25369 Cov.: 32

Gnomad AFR AF: 0.496

Gnomad AMI AF: 0.662

Gnomad AMR AF: 0.440

Gnomad ASJ AF: 0.588

Gnomad EAS AF: 0.332

Gnomad SAS AF: 0.376

Gnomad FIN AF: 0.739

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.640

Gnomad OTH AF: 0.557

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

GnomAD4 genome AF: 0.566 AC: 86055 AN: 152044 Hom.: 25381 Cov.: 32 AF XY: 0.563 AC XY: 41867 AN XY: 74308

African (AFR) AF: 0.496 AC: 20556 AN: 41460

American (AMR) AF: 0.439 AC: 6707 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.588 AC: 2040 AN: 3472

East Asian (EAS) AF: 0.332 AC: 1715 AN: 5170

South Asian (SAS) AF: 0.378 AC: 1820 AN: 4820

European-Finnish (FIN) AF: 0.739 AC: 7804 AN: 10564

Middle Eastern (MID) AF: 0.541 AC: 159 AN: 294

European-Non Finnish (NFE) AF: 0.640 AC: 43470 AN: 67970

Other (OTH) AF: 0.559 AC: 1182 AN: 2114

Alfa AF: 0.513 Hom.: 1645

Bravo AF: 0.540

Asia WGS AF: 0.385 AC: 1338 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.32
DANN	Benign	0.41
PhyloP100		-1.8
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: rs10817082; hg19: chr9-113474166; COSMIC: COSV51881555;