9-110695519-A-T

Position:

• chr9-110695519-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005592.4(MUSK):​c.475A>T​(p.Ser159Cys) 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. 15/21 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)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MUSK NM_005592.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.62

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17578927).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUSK	NM_005592.4	c.475A>T	p.Ser159Cys	missense_variant	4/15	ENST00000374448.9	NP_005583.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUSK	ENST00000374448.9	c.475A>T	p.Ser159Cys	missense_variant	4/15	5	NM_005592.4	ENSP00000363571.4
MUSK	ENST00000416899.7	c.475A>T	p.Ser159Cys	missense_variant	4/14	5		ENSP00000393608.3
MUSK	ENST00000189978.10	c.475A>T	p.Ser159Cys	missense_variant	4/14	5		ENSP00000189978.6
MUSK	ENST00000374439.1	c.169A>T	p.Ser57Cys	missense_variant	2/4	5		ENSP00000363562.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1406512 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 695130

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: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	18
DANN	Benign	0.93
DEOGEN2	Benign	0.35	T;.;.;.;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.27	N
LIST_S2	Uncertain	0.94	D;D;D;D;T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.18	T;T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.4	M;.;M;.;.
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.3	N;N;N;.;.
REVEL	Benign	0.088
Sift	Benign	0.046	D;D;T;.;.
Sift4G	Uncertain	0.054	T;T;T;T;T
Polyphen		0.073	B;.;.;.;.
Vest4		0.27
MutPred		0.52		Loss of disorder (P = 7e-04);Loss of disorder (P = 7e-04);Loss of disorder (P = 7e-04);Loss of disorder (P = 7e-04);.;
MVP		0.74
MPC		0.19
ClinPred		0.30	T
GERP RS		3.4
Varity_R		0.23
gMVP		0.36

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: rs35176182; hg19: chr9-113457799;