9-110668924-T-C

Variant summary

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

The NM_005592.4(MUSK):c.20T>C(p.Ile7Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000821 in 1,461,454 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: MUSK NM_005592.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.78

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 2 ACMG points.

• 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.20T>C	p.Ile7Thr	missense_variant	1/15	ENST00000374448.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUSK	ENST00000374448.9	c.20T>C	p.Ile7Thr	missense_variant	1/15	5	NM_005592.4	P4
MUSK	ENST00000416899.7	c.20T>C	p.Ile7Thr	missense_variant	1/14	5		A1
MUSK	ENST00000189978.10	c.20T>C	p.Ile7Thr	missense_variant	1/14	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461454 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727010

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: 0.0000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Nov 27, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.11	T;.;.;.
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.85	T;T;T;T
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.45	T;T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	0.69	N;.;N;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.66	N;N;N;.
REVEL	Uncertain	0.36
Sift	Benign	0.13	T;T;T;.
Sift4G	Benign	0.17	T;T;T;T
Polyphen		0.70	P;.;.;.
Vest4		0.58
MutPred		0.44		Loss of stability (P = 7e-04);Loss of stability (P = 7e-04);Loss of stability (P = 7e-04);Loss of stability (P = 7e-04);
MVP		0.78
MPC		0.44
ClinPred		0.64	D
GERP RS		5.2
Varity_R		0.099
gMVP		0.58

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: rs2075922654; hg19: chr9-113431204;