NM_005592.4:c.628+22C>G

Variant names:

• chr9-110697488-C-G
• rs41279053
• NM_005592.4:c.628+22C>G

Variant summary

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

The NM_005592.4(MUSK):​c.628+22C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0571 in 1,601,228 control chromosomes in the GnomAD database, including 2,792 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.057 (272 hom., cov: 32)
  • Exomes 𝑓: 0.057 (2520 hom.)
• Consequence: MUSK NM_005592.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.164
• 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), 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 9-110697488-C-G is Benign according to our data. Variant chr9-110697488-C-G is described in ClinVar as Benign. ClinVar VariationId is 259811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0816 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUSK	NM_005592.4	c.628+22C>G		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+22C>G		intron_variant	Intron 5 of 14	5	NM_005592.4	ENSP00000363571.4
MUSK	ENST00000416899.7	c.628+22C>G		intron_variant	Intron 5 of 13	5		ENSP00000393608.3
MUSK	ENST00000189978.10	c.628+22C>G		intron_variant	Intron 5 of 13	5		ENSP00000189978.6
MUSK	ENST00000374439.1	c.322+22C>G		intron_variant	Intron 3 of 3	5		ENSP00000363562.2

Frequencies

GnomAD3 genomes AF: 0.0568 AC: 8635 AN: 152054 Hom.: 271 Cov.: 32

Gnomad AFR AF: 0.0623

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0486

Gnomad ASJ AF: 0.0681

Gnomad EAS AF: 0.0881

Gnomad SAS AF: 0.0723

Gnomad FIN AF: 0.0226

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0569

Gnomad OTH AF: 0.0574

GnomAD2 exomes AF: 0.0583 AC: 14183 AN: 243184 AF XY: 0.0598

Gnomad AFR exome AF: 0.0649

Gnomad AMR exome AF: 0.0343

Gnomad ASJ exome AF: 0.0636

Gnomad EAS exome AF: 0.102

Gnomad FIN exome AF: 0.0270

Gnomad NFE exome AF: 0.0593

Gnomad OTH exome AF: 0.0539

GnomAD4 exome AF: 0.0571 AC: 82775 AN: 1449056 Hom.: 2520 Cov.: 31 AF XY: 0.0580 AC XY: 41748 AN XY: 720186

African (AFR) AF: 0.0635 AC: 2114 AN: 33292

American (AMR) AF: 0.0366 AC: 1607 AN: 43900

Ashkenazi Jewish (ASJ) AF: 0.0627 AC: 1613 AN: 25724

East Asian (EAS) AF: 0.0885 AC: 3478 AN: 39288

South Asian (SAS) AF: 0.0733 AC: 6129 AN: 83648

European-Finnish (FIN) AF: 0.0297 AC: 1568 AN: 52834

Middle Eastern (MID) AF: 0.0588 AC: 338 AN: 5744

European-Non Finnish (NFE) AF: 0.0565 AC: 62435 AN: 1104754

Other (OTH) AF: 0.0583 AC: 3493 AN: 59872

GnomAD4 genome AF: 0.0568 AC: 8644 AN: 152172 Hom.: 272 Cov.: 32 AF XY: 0.0555 AC XY: 4128 AN XY: 74418

African (AFR) AF: 0.0624 AC: 2591 AN: 41504

American (AMR) AF: 0.0486 AC: 742 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0681 AC: 236 AN: 3466

East Asian (EAS) AF: 0.0883 AC: 456 AN: 5162

South Asian (SAS) AF: 0.0717 AC: 346 AN: 4824

European-Finnish (FIN) AF: 0.0226 AC: 240 AN: 10616

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0569 AC: 3869 AN: 68002

Other (OTH) AF: 0.0582 AC: 123 AN: 2112

Alfa AF: 0.0274 Hom.: 28

Bravo AF: 0.0584

Asia WGS AF: 0.0690 AC: 238 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.2
DANN	Benign	0.43
PhyloP100		0.16
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: rs41279053; hg19: chr9-113459768; COSMIC: COSV51892521;