rs56044404

chr9-110734288-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_005592.4(MUSK):c.666T>C(p.Asn222=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00285 in 1,613,162 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (5 hom.)
• Consequence: MUSK NM_005592.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.933

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 9-110734288-T-C is Benign according to our data. Variant chr9-110734288-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 259812.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1, Likely_benign=3}. Variant chr9-110734288-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.933 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00196 (298/152216) while in subpopulation NFE AF= 0.00349 (237/67994). AF 95% confidence interval is 0.00312. There are 0 homozygotes in gnomad4. There are 122 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUSK	NM_005592.4	c.666T>C	p.Asn222=	synonymous_variant	6/15	ENST00000374448.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUSK	ENST00000374448.9	c.666T>C	p.Asn222=	synonymous_variant	6/15	5	NM_005592.4	P4
MUSK	ENST00000416899.7	c.666T>C	p.Asn222=	synonymous_variant	6/14	5		A1
MUSK	ENST00000189978.10	c.696T>C	p.Asn232=	synonymous_variant	7/14	5
MUSK	ENST00000634612.1	n.88T>C		non_coding_transcript_exon_variant	3/6	5

Frequencies

GnomAD3 genomes AF: 0.00196 AC: 298 AN: 152098 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00311

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00349

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00222 AC: 553 AN: 248704 Hom.: 2 AF XY: 0.00221 AC XY: 298 AN XY: 134928

Gnomad AFR exome AF: 0.000324

Gnomad AMR exome AF: 0.000494

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000654

Gnomad FIN exome AF: 0.00348

Gnomad NFE exome AF: 0.00373

Gnomad OTH exome AF: 0.00232

GnomAD4 exome AF: 0.00295 AC: 4307 AN: 1460946 Hom.: 5 Cov.: 31 AF XY: 0.00302 AC XY: 2198 AN XY: 726748

Gnomad4 AFR exome AF: 0.000389

Gnomad4 AMR exome AF: 0.000560

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000626

Gnomad4 FIN exome AF: 0.00399

Gnomad4 NFE exome AF: 0.00349

Gnomad4 OTH exome AF: 0.00187

GnomAD4 genome AF: 0.00196 AC: 298 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.00164 AC XY: 122 AN XY: 74422

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00311

Gnomad4 NFE AF: 0.00349

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00298 Hom.: 0

Bravo AF: 0.00175

EpiCase AF: 0.00278

EpiControl AF: 0.00327

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 19, 2016	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	MUSK: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 10, 2021	- -

Congenital myasthenic syndrome 9 Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Fetal akinesia deformation sequence 1;C4225368:Congenital myasthenic syndrome 9 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
Cadd	Benign	8.9
Dann	Benign	0.70

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: rs56044404; hg19: chr9-113496568;