9-110800329-A-G

Variant names:

• chr9-110800329-A-G
• rs199811263
• NM_005592.4:c.1951A>G

Variant summary

Our verdict is Uncertain significance. The variant received 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M651L) has been classified as Likely benign.

• 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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUSK	NM_005592.4	c.1951A>G	p.Met651Val	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.1951A>G	p.Met651Val	missense_variant	Exon 15 of 15	5	NM_005592.4	ENSP00000363571.4
MUSK	ENST00000416899.7	c.1927A>G	p.Met643Val	missense_variant	Exon 14 of 14	5		ENSP00000393608.3
MUSK	ENST00000189978.10	c.1693A>G	p.Met565Val	missense_variant	Exon 14 of 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

African (AFR) AF: 0.00 AC: 0 AN: 33414

American (AMR) AF: 0.00 AC: 0 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39592

South Asian (SAS) AF: 0.00 AC: 0 AN: 86150

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109446

Other (OTH) AF: 0.0000166 AC: 1 AN: 60212

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;.;.;.
PhyloP100		5.1
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
Mutation Taster		=35/65	disease causing

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Other links and lift over

dbSNP: rs199811263; hg19: chr9-113562609;