rs1311636142

Variant names:

• chr9-110695525-C-T
• rs1311636142
• NM_005592.4:c.481C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4 BP6 BS1

The NM_005592.4(MUSK):​c.481C>T​(p.Leu161Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,554,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: MUSK NM_005592.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.64
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 9

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
• fetal akinesia deformation sequence 1

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.30504328).
• BP6: Variant 9-110695525-C-T is Benign according to our data. Variant chr9-110695525-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 476146.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000178 (25/1402748) while in subpopulation AMR AF = 0.000576 (21/36484). AF 95% confidence interval is 0.000385. There are 0 homozygotes in GnomAdExome4. There are 14 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005592.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUSK	NM_005592.4	MANE Select	c.481C>T	p.Leu161Phe	missense	Exon 4 of 15	NP_005583.1
	MUSK	NM_001166280.2		c.481C>T	p.Leu161Phe	missense	Exon 4 of 14	NP_001159752.1
	MUSK	NM_001166281.2		c.481C>T	p.Leu161Phe	missense	Exon 4 of 13	NP_001159753.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUSK	ENST00000374448.9	TSL:5 MANE Select	c.481C>T	p.Leu161Phe	missense	Exon 4 of 15	ENSP00000363571.4
	MUSK	ENST00000416899.7	TSL:5	c.481C>T	p.Leu161Phe	missense	Exon 4 of 14	ENSP00000393608.3
	MUSK	ENST00000189978.10	TSL:5	c.481C>T	p.Leu161Phe	missense	Exon 4 of 14	ENSP00000189978.6

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000925 AC: 16 AN: 172992 AF XY: 0.000120

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000605

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000137

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 25 AN: 1402748 Hom.: 0 Cov.: 29 AF XY: 0.0000202 AC XY: 14 AN XY: 693010

African (AFR) AF: 0.00 AC: 0 AN: 31874

American (AMR) AF: 0.000576 AC: 21 AN: 36484

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25174

East Asian (EAS) AF: 0.00 AC: 0 AN: 36982

South Asian (SAS) AF: 0.00 AC: 0 AN: 77712

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50546

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1079952

Other (OTH) AF: 0.0000343 AC: 2 AN: 58328

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74314

African (AFR) AF: 0.00 AC: 0 AN: 41424

American (AMR) AF: 0.000196 AC: 3 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000529

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Fetal akinesia deformation sequence 1;C4225368:Congenital myasthenic syndrome 9 (2)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.31	T
MetaSVM	Uncertain	-0.097	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		1.6
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.38
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.29	T
Polyphen		0.97	D
Vest4		0.37
MutPred		0.65		Loss of ubiquitination at K156 (P = 0.1372)
MVP		0.83
MPC		0.64
ClinPred		0.23	T
GERP RS		6.0
Varity_R		0.29
gMVP		0.59
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

dbSNP: rs1311636142; hg19: chr9-113457805;