NM_005592.4:c.2485G>C

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005592.4(MUSK):​c.2485G>C​(p.Val829Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MUSK NM_005592.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.441

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.034250587).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUSK	NM_005592.4	c.2485G>C	p.Val829Leu	missense_variant	Exon 15 of 15	ENST00000374448.9	NP_005583.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUSK	ENST00000374448.9	c.2485G>C	p.Val829Leu	missense_variant	Exon 15 of 15	5	NM_005592.4	ENSP00000363571.4
MUSK	ENST00000416899.7	c.2461G>C	p.Val821Leu	missense_variant	Exon 14 of 14	5		ENSP00000393608.3
MUSK	ENST00000189978.10	c.2227G>C	p.Val743Leu	missense_variant	Exon 14 of 14	5		ENSP00000189978.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.45
DANN	Benign	0.18
DEOGEN2	Benign	0.17	T;.;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.78	T;T;T;T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.034	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.060	N;.;.;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.76	N;.;.;.
REVEL	Benign	0.12
Sift	Benign	1.0	T;.;.;.
Sift4G	Benign	0.44	T;T;T;T
Polyphen		0.0	B;.;.;.
Vest4		0.025
MutPred		0.41		Loss of catalytic residue at V829 (P = 0.0802);.;.;.;
MVP		0.44
MPC		0.16
ClinPred		0.058	T
GERP RS		1.5
Varity_R		0.035
gMVP		0.27

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

LitVar

Other links and lift over

dbSNP: rs578430; hg19: chr9-113563143;