rs387906803

Positions:

• chr9-110767930-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_005592.4(MUSK):​c.1031C>G​(p.Pro344Arg) 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MUSK NM_005592.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.38

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.834
• PP5: Variant 9-110767930-C-G is Pathogenic according to our data. Variant chr9-110767930-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 30175.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr9-110767930-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUSK	NM_005592.4	c.1031C>G	p.Pro344Arg	missense_variant	9/15	ENST00000374448.9	NP_005583.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUSK	ENST00000374448.9	c.1031C>G	p.Pro344Arg	missense_variant	9/15	5	NM_005592.4	ENSP00000363571.4
MUSK	ENST00000416899.7	c.1031C>G	p.Pro344Arg	missense_variant	9/14	5		ENSP00000393608.3
MUSK	ENST00000189978.10	c.950+5722C>G		intron_variant		5		ENSP00000189978.6
MUSK	ENST00000634612.1	n.453C>G		non_coding_transcript_exon_variant	6/6	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Congenital myasthenic syndrome 9 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Uncertain	2.2	M;.
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.4	D;.
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0070	D;.
Sift4G	Benign	0.082	T;T
Polyphen		1.0	D;.
Vest4		0.95
MutPred		0.58		Loss of glycosylation at P344 (P = 0.0907);Loss of glycosylation at P344 (P = 0.0907);
MVP		0.90
MPC		0.69
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.53
gMVP		0.78

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: rs387906803; hg19: chr9-113530210;