9-110800329-A-G

Position:

• chr9-110800329-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005592.4(MUSK):​c.1951A>G​(p.Met651Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,458,638 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MUSK NM_005592.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.12

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUSK	NM_005592.4	c.1951A>G	p.Met651Val	missense_variant	15/15	ENST00000374448.9	NP_005583.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUSK	ENST00000374448.9	c.1951A>G	p.Met651Val	missense_variant	15/15	5	NM_005592.4	ENSP00000363571.4
MUSK	ENST00000416899.7	c.1927A>G	p.Met643Val	missense_variant	14/14	5		ENSP00000393608.3
MUSK	ENST00000189978.10	c.1693A>G	p.Met565Val	missense_variant	14/14	5		ENSP00000189978.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458638 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 724998

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T;.;.;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.86	D;D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.46	T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-0.23	N;.;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.7	D;.;.;.
REVEL	Uncertain	0.32
Sift	Uncertain	0.0050	D;.;.;.
Sift4G	Uncertain	0.014	D;D;D;D
Polyphen		0.98	D;.;.;.
Vest4		0.49
MutPred		0.59		Gain of methylation at K649 (P = 0.1433);.;.;.;
MVP		0.51
MPC		0.24
ClinPred		0.96	D
GERP RS		5.1
Varity_R		0.67
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs199811263; hg19: chr9-113562609;