9-110687128-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_005592.4(MUSK):c.218C>T(p.Thr73Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T73A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MUSK NM_005592.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.36

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 4 ACMG points.

• PM1: In a domain Ig-like 1 (size 88) in uniprot entity MUSK_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_005592.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUSK	NM_005592.4	c.218C>T	p.Thr73Ile	missense_variant	3/15	ENST00000374448.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUSK	ENST00000374448.9	c.218C>T	p.Thr73Ile	missense_variant	3/15	5	NM_005592.4	P4
MUSK	ENST00000416899.7	c.218C>T	p.Thr73Ile	missense_variant	3/14	5		A1
MUSK	ENST00000189978.10	c.218C>T	p.Thr73Ile	missense_variant	3/14	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Fetal akinesia deformation sequence 1;C4225368:Congenital myasthenic syndrome 9 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 30, 2017

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with MUSK-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with isoleucine at codon 73 of the MUSK protein (p.Thr73Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.16	T;.;.;.
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.67	D;D;D;D
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.98	L;.;L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.9	N;N;N;.
REVEL	Benign	0.16
Sift	Uncertain	0.0010	D;D;D;.
Sift4G	Uncertain	0.036	D;D;D;D
Polyphen		0.99	D;.;.;.
Vest4		0.59
MutPred		0.54		Gain of MoRF binding (P = 0.0866);Gain of MoRF binding (P = 0.0866);Gain of MoRF binding (P = 0.0866);Gain of MoRF binding (P = 0.0866);
MVP		0.61
MPC		0.66
ClinPred		0.92	D
GERP RS		5.9
Varity_R		0.51
gMVP		0.54

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: rs750101214; hg19: chr9-113449408;