NM_005592.4:c.206+28A>T

Variant names:

• chr9-110682828-A-T
• rs75001517
• NM_005592.4:c.206+28A>T

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.206+28A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 1,577,430 control chromosomes in the GnomAD database, including 9,718 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.088 (702 hom., cov: 31)
  • Exomes 𝑓: 0.11 (9016 hom.)
• Consequence: MUSK NM_005592.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.66
• Publications: 4 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=-0.89).
• BP6: Variant 9-110682828-A-T is Benign according to our data. Variant chr9-110682828-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 259807.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.122 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUSK	NM_005592.4	c.206+28A>T		intron_variant	Intron 2 of 14	ENST00000374448.9	NP_005583.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUSK	ENST00000374448.9	c.206+28A>T		intron_variant	Intron 2 of 14	5	NM_005592.4	ENSP00000363571.4
MUSK	ENST00000416899.7	c.206+28A>T		intron_variant	Intron 2 of 13	5		ENSP00000393608.3
MUSK	ENST00000189978.10	c.206+28A>T		intron_variant	Intron 2 of 13	5		ENSP00000189978.6

Frequencies

GnomAD3 genomes AF: 0.0881 AC: 13377 AN: 151810 Hom.: 702 Cov.: 31

Gnomad AFR AF: 0.0434

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.0752

Gnomad ASJ AF: 0.0684

Gnomad EAS AF: 0.00790

Gnomad SAS AF: 0.0520

Gnomad FIN AF: 0.114

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.124

Gnomad OTH AF: 0.0864

GnomAD2 exomes AF: 0.0881 AC: 19925 AN: 226282 AF XY: 0.0892

Gnomad AFR exome AF: 0.0465

Gnomad AMR exome AF: 0.0454

Gnomad ASJ exome AF: 0.0627

Gnomad EAS exome AF: 0.00829

Gnomad FIN exome AF: 0.127

Gnomad NFE exome AF: 0.124

Gnomad OTH exome AF: 0.0947

GnomAD4 exome AF: 0.108 AC: 153284 AN: 1425502 Hom.: 9016 Cov.: 25 AF XY: 0.106 AC XY: 75397 AN XY: 709932

African (AFR) AF: 0.0391 AC: 1259 AN: 32212

American (AMR) AF: 0.0486 AC: 2077 AN: 42746

Ashkenazi Jewish (ASJ) AF: 0.0626 AC: 1603 AN: 25618

East Asian (EAS) AF: 0.0117 AC: 453 AN: 38762

South Asian (SAS) AF: 0.0534 AC: 4495 AN: 84140

European-Finnish (FIN) AF: 0.124 AC: 6410 AN: 51814

Middle Eastern (MID) AF: 0.0616 AC: 344 AN: 5586

European-Non Finnish (NFE) AF: 0.121 AC: 131116 AN: 1085692

Other (OTH) AF: 0.0938 AC: 5527 AN: 58932

GnomAD4 genome AF: 0.0881 AC: 13382 AN: 151928 Hom.: 702 Cov.: 31 AF XY: 0.0865 AC XY: 6422 AN XY: 74276

African (AFR) AF: 0.0435 AC: 1804 AN: 41500

American (AMR) AF: 0.0751 AC: 1143 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.0684 AC: 237 AN: 3464

East Asian (EAS) AF: 0.00773 AC: 40 AN: 5176

South Asian (SAS) AF: 0.0519 AC: 250 AN: 4820

European-Finnish (FIN) AF: 0.114 AC: 1206 AN: 10568

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.124 AC: 8422 AN: 67878

Other (OTH) AF: 0.0859 AC: 181 AN: 2106

Alfa AF: 0.103 Hom.: 173

Bravo AF: 0.0793

Asia WGS AF: 0.0360 AC: 123 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Aug 07, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely 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	-0.89
CADD	Benign	0.19
DANN	Benign	0.29
PhyloP100		-1.7
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: rs75001517; hg19: chr9-113445108;