9-110785042-T-C

Variant names:

• chr9-110785042-T-C
• rs484010
• NM_005592.4:c.1586+26T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000374448.9(MUSK):​c.1586+26T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.93 in 1,598,002 control chromosomes in the GnomAD database, including 691,822 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.95 (68308 hom., cov: 33)
  • Exomes 𝑓: 0.93 (623514 hom.)
• Consequence: MUSK ENST00000374448.9 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.303
• Publications: 6 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 9-110785042-T-C is Benign according to our data. Variant chr9-110785042-T-C is described in ClinVar as Benign. ClinVar VariationId is 259801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000374448.9. 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.1586+26T>C		intron	N/A	NP_005583.1
	MUSK	NM_001166280.2		c.1328+26T>C		intron	N/A	NP_001159752.1
	MUSK	NM_001166281.2		c.1298+26T>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.1586+26T>C		intron	N/A	ENSP00000363571.4
	MUSK	ENST00000416899.7	TSL:5	c.1562+26T>C		intron	N/A	ENSP00000393608.3
	MUSK	ENST00000189978.10	TSL:5	c.1328+26T>C		intron	N/A	ENSP00000189978.6

Frequencies

GnomAD3 genomes AF: 0.946 AC: 144018 AN: 152204 Hom.: 68246 Cov.: 33

Gnomad AFR AF: 0.984

Gnomad AMI AF: 0.900

Gnomad AMR AF: 0.946

Gnomad ASJ AF: 0.918

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.970

Gnomad FIN AF: 0.962

Gnomad MID AF: 0.934

Gnomad NFE AF: 0.917

Gnomad OTH AF: 0.943

GnomAD2 exomes AF: 0.945 AC: 234121 AN: 247808 AF XY: 0.943

Gnomad AFR exome AF: 0.988

Gnomad AMR exome AF: 0.966

Gnomad ASJ exome AF: 0.922

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.961

Gnomad NFE exome AF: 0.917

Gnomad OTH exome AF: 0.935

GnomAD4 exome AF: 0.928 AC: 1342153 AN: 1445680 Hom.: 623514 Cov.: 29 AF XY: 0.929 AC XY: 668931 AN XY: 720412

African (AFR) AF: 0.987 AC: 32685 AN: 33108

American (AMR) AF: 0.963 AC: 42992 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.921 AC: 23967 AN: 26012

East Asian (EAS) AF: 1.00 AC: 39597 AN: 39608

South Asian (SAS) AF: 0.963 AC: 82603 AN: 85754

European-Finnish (FIN) AF: 0.961 AC: 50218 AN: 52280

Middle Eastern (MID) AF: 0.929 AC: 5321 AN: 5728

European-Non Finnish (NFE) AF: 0.918 AC: 1008809 AN: 1098676

Other (OTH) AF: 0.935 AC: 55961 AN: 59862

GnomAD4 genome AF: 0.946 AC: 144140 AN: 152322 Hom.: 68308 Cov.: 33 AF XY: 0.949 AC XY: 70714 AN XY: 74480

African (AFR) AF: 0.984 AC: 40897 AN: 41578

American (AMR) AF: 0.946 AC: 14487 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.918 AC: 3188 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5177 AN: 5182

South Asian (SAS) AF: 0.969 AC: 4676 AN: 4824

European-Finnish (FIN) AF: 0.962 AC: 10211 AN: 10612

Middle Eastern (MID) AF: 0.932 AC: 274 AN: 294

European-Non Finnish (NFE) AF: 0.918 AC: 62419 AN: 68030

Other (OTH) AF: 0.944 AC: 1992 AN: 2110

Alfa AF: 0.925 Hom.: 20595

Bravo AF: 0.947

Asia WGS AF: 0.986 AC: 3427 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Congenital myasthenic syndrome 9 (1)
-	-	1	Fetal akinesia deformation sequence 1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	7.8
DANN	Benign	0.49
PhyloP100		0.30
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: rs484010; hg19: chr9-113547322;