rs2274419

Variant names:

• chr9-110775842-G-A
• rs2274419
• NM_005592.4:c.1239G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PVS1_Supporting BP6_Very_Strong BA1

The NM_001369398.1(MUSK):​c.3G>A​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 1,613,518 control chromosomes in the GnomAD database, including 14,411 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.099 (963 hom., cov: 32)
  • Exomes 𝑓: 0.13 (13448 hom.)
• Consequence: MUSK NM_001369398.1 start_lost
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.872
• Publications: 25 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

LOC107987115 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 14 codons. Genomic position: 110775879. Lost 0.030 part of the original CDS.
• BP6: Variant 9-110775842-G-A is Benign according to our data. Variant chr9-110775842-G-A is described in ClinVar as Benign. ClinVar VariationId is 129630.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.191 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001369398.1. 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.1239G>A	p.Met413Ile	missense	Exon 10 of 15	NP_005583.1	O15146-1
	MUSK	NM_001369398.1		c.3G>A	p.Met1?	start_lost	Exon 6 of 10	NP_001356327.1
	MUSK	NM_001166280.2		c.1005G>A	p.Met335Ile	missense	Exon 10 of 14	NP_001159752.1	O15146-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUSK	ENST00000374448.9	TSL:5 MANE Select	c.1239G>A	p.Met413Ile	missense	Exon 10 of 15	ENSP00000363571.4	O15146-1
	MUSK	ENST00000416899.7	TSL:5	c.1239G>A	p.Met413Ile	missense	Exon 10 of 14	ENSP00000393608.3	A0A087WSY1
	MUSK	ENST00000189978.10	TSL:5	c.1005G>A	p.Met335Ile	missense	Exon 10 of 14	ENSP00000189978.6	O15146-2

Frequencies

GnomAD3 genomes AF: 0.0988 AC: 15021 AN: 151960 Hom.: 964 Cov.: 32

Gnomad AFR AF: 0.0223

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.0551

Gnomad ASJ AF: 0.103

Gnomad EAS AF: 0.201

Gnomad SAS AF: 0.147

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.0705

GnomAD2 exomes AF: 0.120 AC: 29807 AN: 249200 AF XY: 0.124

Gnomad AFR exome AF: 0.0197

Gnomad AMR exome AF: 0.0403

Gnomad ASJ exome AF: 0.0978

Gnomad EAS exome AF: 0.196

Gnomad FIN exome AF: 0.158

Gnomad NFE exome AF: 0.133

Gnomad OTH exome AF: 0.107

GnomAD4 exome AF: 0.132 AC: 192302 AN: 1461440 Hom.: 13448 Cov.: 32 AF XY: 0.133 AC XY: 96646 AN XY: 727022

African (AFR) AF: 0.0172 AC: 577 AN: 33476

American (AMR) AF: 0.0413 AC: 1846 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.100 AC: 2622 AN: 26132

East Asian (EAS) AF: 0.224 AC: 8878 AN: 39694

South Asian (SAS) AF: 0.148 AC: 12732 AN: 86256

European-Finnish (FIN) AF: 0.158 AC: 8439 AN: 53398

Middle Eastern (MID) AF: 0.0570 AC: 329 AN: 5768

European-Non Finnish (NFE) AF: 0.135 AC: 150152 AN: 1111628

Other (OTH) AF: 0.111 AC: 6727 AN: 60372

GnomAD4 genome AF: 0.0988 AC: 15020 AN: 152078 Hom.: 963 Cov.: 32 AF XY: 0.100 AC XY: 7443 AN XY: 74350

African (AFR) AF: 0.0223 AC: 925 AN: 41516

American (AMR) AF: 0.0550 AC: 841 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 356 AN: 3468

East Asian (EAS) AF: 0.201 AC: 1039 AN: 5160

South Asian (SAS) AF: 0.148 AC: 710 AN: 4810

European-Finnish (FIN) AF: 0.156 AC: 1650 AN: 10564

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.135 AC: 9191 AN: 67962

Other (OTH) AF: 0.0707 AC: 149 AN: 2108

Alfa AF: 0.116 Hom.: 2562

Bravo AF: 0.0861

TwinsUK AF: 0.135 AC: 501

ALSPAC AF: 0.137 AC: 527

ESP6500AA AF: 0.0219 AC: 83

ESP6500EA AF: 0.133 AC: 1094

ExAC AF: 0.121 AC: 14602

Asia WGS AF: 0.162 AC: 562 AN: 3478

EpiCase AF: 0.127

EpiControl AF: 0.120

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	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	Pathogenic	0.62
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	16
DANN	Benign	0.91
DEOGEN2	Benign	0.075	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.47
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.88	L
PhyloP100		0.87
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.063
Sift	Benign	0.60	T
Sift4G	Benign	0.50	T
Polyphen		0.0	B
Vest4		0.048
MutPred		0.48		Gain of methylation at K416 (P = 0.0832)
MPC		0.18
ClinPred		0.0050	T
GERP RS		1.1
Varity_R		0.052
gMVP		0.23
Mutation Taster		=81/19	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: rs2274419; hg19: chr9-113538122; COSMIC: COSV51886200;