9-110800863-G-T

Variant names:

• chr9-110800863-G-T
• rs578430
• NM_005592.4:c.2485G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005592.4(MUSK):​c.2485G>T​(p.Val829Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0351 in 1,600,684 control chromosomes in the GnomAD database, including 3,194 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V829M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.087 (1376 hom., cov: 32)
  • Exomes 𝑓: 0.030 (1818 hom.)
• Consequence: MUSK NM_005592.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.441
• Publications: 17 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=0.0020249784).
• BP6: Variant 9-110800863-G-T is Benign according to our data. Variant chr9-110800863-G-T is described in ClinVar as Benign. ClinVar VariationId is 129633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.24 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUSK	NM_005592.4	MANE Select	c.2485G>T	p.Val829Leu	missense	Exon 15 of 15	NP_005583.1
	MUSK	NM_001166280.2		c.2227G>T	p.Val743Leu	missense	Exon 14 of 14	NP_001159752.1
	MUSK	NM_001166281.2		c.2197G>T	p.Val733Leu	missense	Exon 13 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.2485G>T	p.Val829Leu	missense	Exon 15 of 15	ENSP00000363571.4
	MUSK	ENST00000416899.7	TSL:5	c.2461G>T	p.Val821Leu	missense	Exon 14 of 14	ENSP00000393608.3
	MUSK	ENST00000189978.10	TSL:5	c.2227G>T	p.Val743Leu	missense	Exon 14 of 14	ENSP00000189978.6

Frequencies

GnomAD3 genomes AF: 0.0870 AC: 13227 AN: 152090 Hom.: 1373 Cov.: 32

Gnomad AFR AF: 0.244

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0487

Gnomad ASJ AF: 0.0536

Gnomad EAS AF: 0.0282

Gnomad SAS AF: 0.0625

Gnomad FIN AF: 0.00641

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0217

Gnomad OTH AF: 0.0793

GnomAD2 exomes AF: 0.0433 AC: 10349 AN: 238816 AF XY: 0.0415

Gnomad AFR exome AF: 0.246

Gnomad AMR exome AF: 0.0301

Gnomad ASJ exome AF: 0.0533

Gnomad EAS exome AF: 0.0241

Gnomad FIN exome AF: 0.00736

Gnomad NFE exome AF: 0.0217

Gnomad OTH exome AF: 0.0425

GnomAD4 exome AF: 0.0296 AC: 42854 AN: 1448476 Hom.: 1818 Cov.: 32 AF XY: 0.0303 AC XY: 21767 AN XY: 718872

African (AFR) AF: 0.258 AC: 8529 AN: 33120

American (AMR) AF: 0.0309 AC: 1360 AN: 43988

Ashkenazi Jewish (ASJ) AF: 0.0552 AC: 1386 AN: 25090

East Asian (EAS) AF: 0.0299 AC: 1185 AN: 39574

South Asian (SAS) AF: 0.0673 AC: 5667 AN: 84192

European-Finnish (FIN) AF: 0.00689 AC: 364 AN: 52820

Middle Eastern (MID) AF: 0.0827 AC: 472 AN: 5704

European-Non Finnish (NFE) AF: 0.0193 AC: 21329 AN: 1104198

Other (OTH) AF: 0.0428 AC: 2562 AN: 59790

GnomAD4 genome AF: 0.0871 AC: 13255 AN: 152208 Hom.: 1376 Cov.: 32 AF XY: 0.0850 AC XY: 6326 AN XY: 74416

African (AFR) AF: 0.244 AC: 10125 AN: 41498

American (AMR) AF: 0.0486 AC: 744 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0536 AC: 186 AN: 3472

East Asian (EAS) AF: 0.0286 AC: 148 AN: 5172

South Asian (SAS) AF: 0.0617 AC: 298 AN: 4828

European-Finnish (FIN) AF: 0.00641 AC: 68 AN: 10602

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0217 AC: 1479 AN: 68010

Other (OTH) AF: 0.0814 AC: 172 AN: 2114

Alfa AF: 0.0422 Hom.: 1952

Bravo AF: 0.0971

TwinsUK AF: 0.0216 AC: 80

ALSPAC AF: 0.0176 AC: 68

ESP6500AA AF: 0.242 AC: 1001

ESP6500EA AF: 0.0220 AC: 184

ExAC AF: 0.0470 AC: 5683

Asia WGS AF: 0.0550 AC: 192 AN: 3478

ClinVar

ClinVar submissions as Germline

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
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.43
DANN	Benign	0.17
DEOGEN2	Benign	0.17	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.060	N
PhyloP100		0.44
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.76	N
REVEL	Benign	0.13
Sift	Benign	1.0	T
Sift4G	Benign	0.44	T
Polyphen		0.0	B
Vest4		0.025
MutPred		0.41		Loss of catalytic residue at V829 (P = 0.0802)
MPC		0.16
ClinPred		0.00018	T
GERP RS		1.5
Varity_R		0.035
gMVP		0.27
Mutation Taster		=96/4	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: rs578430; hg19: chr9-113563143; COSMIC: COSV51893593;