Genetic Variant MUSK:c.1184+1222T>C (chr9-110769305-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005592.4(MUSK):c.1184+1222T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.828 in 152,120 control chromosomes in the GnomAD database, including 52,391 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 0.83 ( 52391 hom., cov: 32)

Consequence

MUSK
NM_005592.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.23

Publications

4 publications found

Variant links:

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

MUSK links:

LOC107987115 (HGNC:):

LOC107987115 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.94).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.898 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUSK	NM_005592.4 link	c.1184+1222T>C		intron_variant	Intron 9 of 14	ENST00000374448.9	NP_005583.1	O15146-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
MUSK	ENST00000374448.9 link	c.1184+1222T>C	intron_variant	Intron 9 of 14	5	NM_005592.4	ENSP00000363571.4	O15146-1
MUSK	ENST00000416899.7 link	c.1184+1222T>C	intron_variant	Intron 9 of 13	5		ENSP00000393608.3	A0A087WSY1
MUSK	ENST00000189978.10 link	c.951-6483T>C	intron_variant	Intron 9 of 13	5		ENSP00000189978.6	O15146-2

Frequencies

GnomAD3 genomes

AF:

0.828

AC:

125868

AN:

152002

Hom.:

52348

Cov.:

show subpopulations

Gnomad AFR

AF:

0.905

Gnomad AMI

AF:

0.851

Gnomad AMR

AF:

0.765

Gnomad ASJ

AF:

0.780

Gnomad EAS

AF:

0.681

Gnomad SAS

AF:

0.805

Gnomad FIN

AF:

0.814

Gnomad MID

AF:

0.788

Gnomad NFE

AF:

0.813

Gnomad OTH

AF:

0.809

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

GnomAD4 genome

AF:

0.828

AC:

125973

AN:

152120

Hom.:

52391

Cov.:

AF XY:

0.826

AC XY:

61461

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.905

AC:

37590

AN:

41522

American (AMR)

AF:

0.764

AC:

11687

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.780

AC:

2699

AN:

3462

East Asian (EAS)

AF:

0.681

AC:

3522

AN:

5172

South Asian (SAS)

AF:

0.804

AC:

3873

AN:

4816

European-Finnish (FIN)

AF:

0.814

AC:

8622

AN:

10586

Middle Eastern (MID)

AF:

0.776

AC:

228

AN:

294

European-Non Finnish (NFE)

AF:

0.813

AC:

55267

AN:

67964

Other (OTH)

AF:

0.812

AC:

1712

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1115

2229

3344

4458

5573

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.815

Hom.:

213102

Bravo

AF:

0.827

Asia WGS

AF:

0.752

AC:

2610

AN:

3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

0.29

(source)

DANN

Benign

0.48

PhyloP100

-1.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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9-110769305-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over