rs138418494

Variant names:

• chr9-110800581-G-A
• rs138418494
• NM_005592.4:c.2203G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_005592.4(MUSK):​c.2203G>A​(p.Glu735Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000609 in 1,609,884 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00063 (0 hom.)
• Consequence: MUSK NM_005592.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1
• Conservation: PhyloP100: 5.03
• Publications: 4 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18807405).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00039 (59/151464) while in subpopulation NFE AF = 0.000737 (50/67880). AF 95% confidence interval is 0.000574. There are 0 homozygotes in GnomAd4. There are 28 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.2203G>A	p.Glu735Lys	missense	Exon 15 of 15	NP_005583.1
	MUSK	NM_001166280.2		c.1945G>A	p.Glu649Lys	missense	Exon 14 of 14	NP_001159752.1
	MUSK	NM_001166281.2		c.1915G>A	p.Glu639Lys	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.2203G>A	p.Glu735Lys	missense	Exon 15 of 15	ENSP00000363571.4
	MUSK	ENST00000416899.7	TSL:5	c.2179G>A	p.Glu727Lys	missense	Exon 14 of 14	ENSP00000393608.3
	MUSK	ENST00000189978.10	TSL:5	c.1945G>A	p.Glu649Lys	missense	Exon 14 of 14	ENSP00000189978.6

Frequencies

GnomAD3 genomes AF: 0.000390 AC: 59 AN: 151344 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000264

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000737

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000329 AC: 82 AN: 249242 AF XY: 0.000355

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000655

Gnomad OTH exome AF: 0.000661

GnomAD4 exome AF: 0.000632 AC: 921 AN: 1458420 Hom.: 0 Cov.: 32 AF XY: 0.000655 AC XY: 475 AN XY: 725450

African (AFR) AF: 0.000150 AC: 5 AN: 33368

American (AMR) AF: 0.000112 AC: 5 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26018

East Asian (EAS) AF: 0.00 AC: 0 AN: 39582

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86216

European-Finnish (FIN) AF: 0.0000378 AC: 2 AN: 52934

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.000796 AC: 883 AN: 1109804

Other (OTH) AF: 0.000416 AC: 25 AN: 60144

GnomAD4 genome AF: 0.000390 AC: 59 AN: 151464 Hom.: 0 Cov.: 32 AF XY: 0.000378 AC XY: 28 AN XY: 73990

African (AFR) AF: 0.000121 AC: 5 AN: 41330

American (AMR) AF: 0.000263 AC: 4 AN: 15182

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5056

South Asian (SAS) AF: 0.00 AC: 0 AN: 4728

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10520

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000737 AC: 50 AN: 67880

Other (OTH) AF: 0.00 AC: 0 AN: 2104

Alfa AF: 0.000625 Hom.: 0

Bravo AF: 0.000434

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000252 AC: 1

ESP6500EA AF: 0.000360 AC: 3

ExAC AF: 0.000314 AC: 38

EpiCase AF: 0.00115

EpiControl AF: 0.000948

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	5	-	not provided (5)
-	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
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	0.40	N
PhyloP100		5.0
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.53
Sift	Benign	0.098	T
Sift4G	Uncertain	0.010	D
Polyphen		0.90	P
Vest4		0.58
MVP		0.86
MPC		0.42
ClinPred		0.24	T
GERP RS		3.6
Varity_R		0.40
gMVP		0.78
Mutation Taster		=70/30	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: rs138418494; hg19: chr9-113562861; COSMIC: COSV99503968;