NM_005592.4:c.320G>A

Variant names:

• chr9-110687230-G-A
• rs55786136
• NM_005592.4:c.320G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005592.4(MUSK):​c.320G>A​(p.Gly107Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00326 in 1,613,842 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0033 (11 hom.)
• Consequence: MUSK NM_005592.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.03
• Publications: 10 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 (MetaRNN=0.0066536367).
• BP6: Variant 9-110687230-G-A is Benign according to our data. Variant chr9-110687230-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259809.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 = 0.00325 (495/152274) while in subpopulation NFE AF = 0.00393 (267/68024). AF 95% confidence interval is 0.00354. There are 0 homozygotes in GnomAd4. There are 282 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 11 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUSK	NM_005592.4	MANE Select	c.320G>A	p.Gly107Glu	missense	Exon 3 of 15	NP_005583.1
	MUSK	NM_001166280.2		c.320G>A	p.Gly107Glu	missense	Exon 3 of 14	NP_001159752.1
	MUSK	NM_001166281.2		c.320G>A	p.Gly107Glu	missense	Exon 3 of 13	NP_001159753.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUSK	ENST00000374448.9	TSL:5 MANE Select	c.320G>A	p.Gly107Glu	missense	Exon 3 of 15	ENSP00000363571.4
	MUSK	ENST00000416899.7	TSL:5	c.320G>A	p.Gly107Glu	missense	Exon 3 of 14	ENSP00000393608.3
	MUSK	ENST00000189978.10	TSL:5	c.320G>A	p.Gly107Glu	missense	Exon 3 of 14	ENSP00000189978.6

Frequencies

GnomAD3 genomes AF: 0.00325 AC: 494 AN: 152156 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0139

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00392

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00350 AC: 873 AN: 249238 AF XY: 0.00341

Gnomad AFR exome AF: 0.000517

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0129

Gnomad NFE exome AF: 0.00450

Gnomad OTH exome AF: 0.00363

GnomAD4 exome AF: 0.00326 AC: 4770 AN: 1461568 Hom.: 11 Cov.: 31 AF XY: 0.00320 AC XY: 2328 AN XY: 727060

African (AFR) AF: 0.000568 AC: 19 AN: 33474

American (AMR) AF: 0.00150 AC: 67 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86254

European-Finnish (FIN) AF: 0.0126 AC: 671 AN: 53392

Middle Eastern (MID) AF: 0.00486 AC: 28 AN: 5764

European-Non Finnish (NFE) AF: 0.00340 AC: 3784 AN: 1111770

Other (OTH) AF: 0.00295 AC: 178 AN: 60366

GnomAD4 genome AF: 0.00325 AC: 495 AN: 152274 Hom.: 0 Cov.: 31 AF XY: 0.00379 AC XY: 282 AN XY: 74456

African (AFR) AF: 0.000457 AC: 19 AN: 41544

American (AMR) AF: 0.00275 AC: 42 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.0139 AC: 148 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00393 AC: 267 AN: 68024

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00331 Hom.: 7

Bravo AF: 0.00226

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000491 AC: 2

ESP6500EA AF: 0.00369 AC: 31

ExAC AF: 0.00366 AC: 443

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00322

EpiControl AF: 0.00356

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	18
DANN	Benign	0.52
DEOGEN2	Benign	0.062	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0067	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	-1.0	N
PhyloP100		2.0
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.18
Sift	Benign	0.54	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.18
MVP		0.68
MPC		0.21
ClinPred		0.013	T
GERP RS		4.1
PromoterAI		0.00090	Neutral
Varity_R		0.077
gMVP		0.56
Mutation Taster		=285/15	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: rs55786136; hg19: chr9-113449510;