9-110668823-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_005592.4(MUSK):c.-82T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0173 in 1,082,916 control chromosomes in the GnomAD database, including 288 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (39 hom., cov: 32)
  • Exomes 𝑓: 0.018 (249 hom.)
• Consequence: MUSK NM_005592.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.482

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 9-110668823-T-C is Benign according to our data. Variant chr9-110668823-T-C is described in ClinVar as [Benign]. Clinvar id is 364595.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0148 (2255/152260) while in subpopulation NFE AF= 0.0162 (1104/68012). AF 95% confidence interval is 0.0154. There are 39 homozygotes in gnomad4. There are 1272 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 39 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUSK	NM_005592.4	c.-82T>C		5_prime_UTR_variant	1/15	ENST00000374448.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUSK	ENST00000374448.9	c.-82T>C		5_prime_UTR_variant	1/15	5	NM_005592.4	P4
MUSK	ENST00000416899.7	c.-82T>C		5_prime_UTR_variant	1/14	5		A1
MUSK	ENST00000189978.10			upstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.0148 AC: 2258 AN: 152142 Hom.: 39 Cov.: 32

Gnomad AFR AF: 0.00309

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0104

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00869

Gnomad FIN AF: 0.0736

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0162

Gnomad OTH AF: 0.0120

GnomAD4 exome AF: 0.0177 AC: 16483 AN: 930656 Hom.: 249 Cov.: 13 AF XY: 0.0174 AC XY: 8387 AN XY: 481696

Gnomad4 AFR exome AF: 0.00354

Gnomad4 AMR exome AF: 0.00809

Gnomad4 ASJ exome AF: 0.00574

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0108

Gnomad4 FIN exome AF: 0.0672

Gnomad4 NFE exome AF: 0.0173

Gnomad4 OTH exome AF: 0.0148

GnomAD4 genome AF: 0.0148 AC: 2255 AN: 152260 Hom.: 39 Cov.: 32 AF XY: 0.0171 AC XY: 1272 AN XY: 74436

Gnomad4 AFR AF: 0.00308

Gnomad4 AMR AF: 0.0103

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00891

Gnomad4 FIN AF: 0.0736

Gnomad4 NFE AF: 0.0162

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.0140 Hom.: 1

Bravo AF: 0.00967

Asia WGS AF: 0.00289 AC: 11 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 05, 2018

- -

Congenital myasthenic syndrome 9 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
Cadd	Benign	11
Dann	Benign	0.80

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

LitVar

Other links and lift over

dbSNP: rs41279047; hg19: chr9-113431103;