rs56044404

Variant names:

• chr9-110734288-T-C
• rs56044404
• NM_005592.4:c.666T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_005592.4(MUSK):​c.666T>C​(p.Asn222Asn) 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
• Publications: 0 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 -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 VariationId is 259812.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005592.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUSK	NM_005592.4	MANE Select	c.666T>C	p.Asn222Asn	synonymous	Exon 6 of 15	NP_005583.1
	MUSK	NM_001166280.2		c.696T>C	p.Asn232Asn	synonymous	Exon 7 of 14	NP_001159752.1
	MUSK	NM_001166281.2		c.666T>C	p.Asn222Asn	synonymous	Exon 6 of 13	NP_001159753.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUSK	ENST00000374448.9	TSL:5 MANE Select	c.666T>C	p.Asn222Asn	synonymous	Exon 6 of 15	ENSP00000363571.4
	MUSK	ENST00000416899.7	TSL:5	c.666T>C	p.Asn222Asn	synonymous	Exon 6 of 14	ENSP00000393608.3
	MUSK	ENST00000189978.10	TSL:5	c.696T>C	p.Asn232Asn	synonymous	Exon 7 of 14	ENSP00000189978.6

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

GnomAD2 exomes AF: 0.00222 AC: 553 AN: 248704 AF XY: 0.00221

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 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

African (AFR) AF: 0.000389 AC: 13 AN: 33400

American (AMR) AF: 0.000560 AC: 25 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.000626 AC: 54 AN: 86214

European-Finnish (FIN) AF: 0.00399 AC: 213 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00349 AC: 3883 AN: 1111434

Other (OTH) AF: 0.00187 AC: 113 AN: 60334

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

African (AFR) AF: 0.000457 AC: 19 AN: 41552

American (AMR) AF: 0.000327 AC: 5 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4824

European-Finnish (FIN) AF: 0.00311 AC: 33 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00349 AC: 237 AN: 67994

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00274 Hom.: 0

Bravo AF: 0.00175

EpiCase AF: 0.00278

EpiControl AF: 0.00327

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	1	-	Congenital myasthenic syndrome 9 (1)
-	-	1	Fetal akinesia deformation sequence 1;C4225368:Congenital myasthenic syndrome 9 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	8.9
DANN	Benign	0.70
PhyloP100		0.93
Mutation Taster		=99/1	polymorphism

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: rs56044404; hg19: chr9-113496568;