NM_005592.4:c.557G>A

Variant names:

• chr9-110697395-G-A
• rs373304727
• NM_005592.4:c.557G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005592.4(MUSK):​c.557G>A​(p.Gly186Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G186A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MUSK NM_005592.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.43
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.863

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUSK	NM_005592.4	c.557G>A	p.Gly186Glu	missense_variant	Exon 5 of 15	ENST00000374448.9	NP_005583.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUSK	ENST00000374448.9	c.557G>A	p.Gly186Glu	missense_variant	Exon 5 of 15	5	NM_005592.4	ENSP00000363571.4
MUSK	ENST00000416899.7	c.557G>A	p.Gly186Glu	missense_variant	Exon 5 of 14	5		ENSP00000393608.3
MUSK	ENST00000189978.10	c.557G>A	p.Gly186Glu	missense_variant	Exon 5 of 14	5		ENSP00000189978.6
MUSK	ENST00000374439.1	c.251G>A	p.Gly84Glu	missense_variant	Exon 3 of 4	5		ENSP00000363562.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jan 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.557G>A (p.G186E) alteration is located in exon 5 (coding exon 5) of the MUSK gene. This alteration results from a G to A substitution at nucleotide position 557, causing the glycine (G) at amino acid position 186 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;.;.;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D;D;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Pathogenic	4.7	H;.;H;.;.
PhyloP100		8.4
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.3	D;D;D;.;.
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D;D;D;.;.
Sift4G	Uncertain	0.0040	D;D;T;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.98
MutPred		0.69		Gain of disorder (P = 0.0681);Gain of disorder (P = 0.0681);Gain of disorder (P = 0.0681);Gain of disorder (P = 0.0681);.;
MVP		0.90
MPC		0.78
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.97
gMVP		0.93
Mutation Taster		=25/75	disease causing

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: rs373304727; hg19: chr9-113459675;