9-110695446-G-A

Variant names:

• chr9-110695446-G-A
• rs10980531
• NM_005592.4:c.402G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005592.4(MUSK):​c.402G>A​(p.Glu134Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.175 in 1,535,178 control chromosomes in the GnomAD database, including 24,102 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2166 hom., cov: 33)
  • Exomes 𝑓: 0.18 (21936 hom.)
• Consequence: MUSK NM_005592.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.227
• Publications: 9 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)
• fetal akinesia deformation sequence 1

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 9-110695446-G-A is Benign according to our data. Variant chr9-110695446-G-A is described in ClinVar as Benign. ClinVar VariationId is 129635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.227 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.203 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUSK	NM_005592.4	MANE Select	c.402G>A	p.Glu134Glu	synonymous	Exon 4 of 15	NP_005583.1	O15146-1
	MUSK	NM_001166280.2		c.402G>A	p.Glu134Glu	synonymous	Exon 4 of 14	NP_001159752.1	O15146-2
	MUSK	NM_001166281.2		c.402G>A	p.Glu134Glu	synonymous	Exon 4 of 13	NP_001159753.1	O15146-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUSK	ENST00000374448.9	TSL:5 MANE Select	c.402G>A	p.Glu134Glu	synonymous	Exon 4 of 15	ENSP00000363571.4	O15146-1
	MUSK	ENST00000416899.7	TSL:5	c.402G>A	p.Glu134Glu	synonymous	Exon 4 of 14	ENSP00000393608.3	A0A087WSY1
	MUSK	ENST00000189978.10	TSL:5	c.402G>A	p.Glu134Glu	synonymous	Exon 4 of 14	ENSP00000189978.6	O15146-2

Frequencies

GnomAD3 genomes AF: 0.166 AC: 25184 AN: 151970 Hom.: 2163 Cov.: 33

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.0758

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.214

Gnomad SAS AF: 0.184

Gnomad FIN AF: 0.145

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.187

Gnomad OTH AF: 0.160

GnomAD2 exomes AF: 0.159 AC: 27829 AN: 175058 AF XY: 0.163

Gnomad AFR exome AF: 0.131

Gnomad AMR exome AF: 0.0848

Gnomad ASJ exome AF: 0.132

Gnomad EAS exome AF: 0.212

Gnomad FIN exome AF: 0.157

Gnomad NFE exome AF: 0.178

Gnomad OTH exome AF: 0.164

GnomAD4 exome AF: 0.176 AC: 242898 AN: 1383090 Hom.: 21936 Cov.: 27 AF XY: 0.176 AC XY: 120764 AN XY: 684428

African (AFR) AF: 0.135 AC: 4275 AN: 31700

American (AMR) AF: 0.0927 AC: 3411 AN: 36788

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 3300 AN: 25062

East Asian (EAS) AF: 0.226 AC: 8410 AN: 37210

South Asian (SAS) AF: 0.180 AC: 13913 AN: 77094

European-Finnish (FIN) AF: 0.160 AC: 8063 AN: 50508

Middle Eastern (MID) AF: 0.160 AC: 905 AN: 5668

European-Non Finnish (NFE) AF: 0.180 AC: 190766 AN: 1061362

Other (OTH) AF: 0.171 AC: 9855 AN: 57698

GnomAD4 genome AF: 0.166 AC: 25199 AN: 152088 Hom.: 2166 Cov.: 33 AF XY: 0.164 AC XY: 12180 AN XY: 74334

African (AFR) AF: 0.142 AC: 5890 AN: 41482

American (AMR) AF: 0.139 AC: 2128 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 489 AN: 3468

East Asian (EAS) AF: 0.214 AC: 1106 AN: 5172

South Asian (SAS) AF: 0.183 AC: 883 AN: 4820

European-Finnish (FIN) AF: 0.145 AC: 1536 AN: 10572

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.187 AC: 12709 AN: 67982

Other (OTH) AF: 0.161 AC: 341 AN: 2116

Alfa AF: 0.173 Hom.: 1212

Bravo AF: 0.159

Asia WGS AF: 0.185 AC: 640 AN: 3472

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Congenital myasthenic syndrome 9 (1)
-	-	1	Fetal akinesia deformation sequence 1;C4225368:Congenital myasthenic syndrome 9 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	4.1
DANN	Benign	0.49
PhyloP100		0.23
Mutation Taster		=92/8	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: rs10980531; hg19: chr9-113457726; COSMIC: COSV51879561;