rs751889864

Positions:

• chr9-110785664-T-A
• chr9-110785664-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_005592.4(MUSK):​c.1724T>A​(p.Ile575Asn) 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. 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. I575T) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MUSK NM_005592.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.67

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]

LOC107987115 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-110785664-T-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUSK	NM_005592.4	c.1724T>A	p.Ile575Asn	missense_variant	13/15	ENST00000374448.9	NP_005583.1
LOC107987115	XR_001746892.2	n.28A>T		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUSK	ENST00000374448.9	c.1724T>A	p.Ile575Asn	missense_variant	13/15	5	NM_005592.4	ENSP00000363571	P4
MUSK	ENST00000416899.7	c.1700T>A	p.Ile567Asn	missense_variant	12/14	5		ENSP00000393608	A1
MUSK	ENST00000189978.10	c.1466T>A	p.Ile489Asn	missense_variant	12/14	5		ENSP00000189978
MUSK	ENST00000374438.1	n.755T>A		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248956 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135068

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000827 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D;.;.;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Uncertain	2.8	M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.6	D;.;.;.
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.96
MutPred		0.76		Gain of disorder (P = 0.014);.;.;.;
MVP		0.97
MPC		0.93
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.93
gMVP		0.89

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: rs751889864; hg19: chr9-113547944;