9-110695446-G-C

Variant names:

• chr9-110695446-G-C
• NM_005592.4:c.402G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005592.4(MUSK):​c.402G>C​(p.Glu134Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000721 in 1,386,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E134E) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: MUSK NM_005592.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.227

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3177547).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUSK	NM_005592.4	c.402G>C	p.Glu134Asp	missense_variant	Exon 4 of 15	ENST00000374448.9	NP_005583.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUSK	ENST00000374448.9	c.402G>C	p.Glu134Asp	missense_variant	Exon 4 of 15	5	NM_005592.4	ENSP00000363571.4
MUSK	ENST00000416899.7	c.402G>C	p.Glu134Asp	missense_variant	Exon 4 of 14	5		ENSP00000393608.3
MUSK	ENST00000189978.10	c.402G>C	p.Glu134Asp	missense_variant	Exon 4 of 14	5		ENSP00000189978.6
MUSK	ENST00000374439.1	c.96G>C	p.Glu32Asp	missense_variant	Exon 2 of 4	5		ENSP00000363562.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.21e-7 AC: 1 AN: 1386614 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 686088

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.40e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;.;.;.;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.95	D;D;D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.32	T;T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.6	M;.;M;.;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.1	N;N;N;.;.
REVEL	Benign	0.18
Sift	Benign	0.22	T;T;D;.;.
Sift4G	Benign	0.28	T;T;T;T;T
Polyphen		0.87	P;.;.;.;.
Vest4		0.40
MutPred		0.54		Loss of methylation at K131 (P = 0.09);Loss of methylation at K131 (P = 0.09);Loss of methylation at K131 (P = 0.09);Loss of methylation at K131 (P = 0.09);.;
MVP		0.30
MPC		0.54
ClinPred		0.91	D
GERP RS		-1.2
Varity_R		0.13
gMVP		0.71

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-113457726;