rs35142681

Variant names:

• chr9-110687209-C-T
• rs35142681
• NM_005592.4:c.299C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005592.4(MUSK):​c.299C>T​(p.Thr100Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0269 in 1,613,722 control chromosomes in the GnomAD database, including 711 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T100T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.021 (44 hom., cov: 31)
  • Exomes 𝑓: 0.027 (667 hom.)
• Consequence: MUSK NM_005592.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.213
• Publications: 19 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)
• fetal akinesia deformation sequence 1

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0064065754).
• BP6: Variant 9-110687209-C-T is Benign according to our data. Variant chr9-110687209-C-T is described in ClinVar as Benign. ClinVar VariationId is 129634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0213 (3236/152218) while in subpopulation NFE AF = 0.0324 (2206/68016). AF 95% confidence interval is 0.0313. There are 44 homozygotes in GnomAd4. There are 1504 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 44 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUSK	NM_005592.4	MANE Select	c.299C>T	p.Thr100Met	missense	Exon 3 of 15	NP_005583.1	O15146-1
	MUSK	NM_001166280.2		c.299C>T	p.Thr100Met	missense	Exon 3 of 14	NP_001159752.1	O15146-2
	MUSK	NM_001166281.2		c.299C>T	p.Thr100Met	missense	Exon 3 of 13	NP_001159753.1	O15146-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUSK	ENST00000374448.9	TSL:5 MANE Select	c.299C>T	p.Thr100Met	missense	Exon 3 of 15	ENSP00000363571.4	O15146-1
	MUSK	ENST00000416899.7	TSL:5	c.299C>T	p.Thr100Met	missense	Exon 3 of 14	ENSP00000393608.3	A0A087WSY1
	MUSK	ENST00000189978.10	TSL:5	c.299C>T	p.Thr100Met	missense	Exon 3 of 14	ENSP00000189978.6	O15146-2

Frequencies

GnomAD3 genomes AF: 0.0213 AC: 3236 AN: 152100 Hom.: 44 Cov.: 31

Gnomad AFR AF: 0.00625

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0191

Gnomad ASJ AF: 0.0259

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.0290

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0324

Gnomad OTH AF: 0.0196

GnomAD2 exomes AF: 0.0230 AC: 5741 AN: 249182 AF XY: 0.0230

Gnomad AFR exome AF: 0.00568

Gnomad AMR exome AF: 0.0123

Gnomad ASJ exome AF: 0.0276

Gnomad EAS exome AF: 0.00362

Gnomad FIN exome AF: 0.0310

Gnomad NFE exome AF: 0.0348

Gnomad OTH exome AF: 0.0246

GnomAD4 exome AF: 0.0274 AC: 40103 AN: 1461504 Hom.: 667 Cov.: 31 AF XY: 0.0269 AC XY: 19524 AN XY: 727020

African (AFR) AF: 0.00463 AC: 155 AN: 33474

American (AMR) AF: 0.0125 AC: 561 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0253 AC: 661 AN: 26134

East Asian (EAS) AF: 0.00146 AC: 58 AN: 39698

South Asian (SAS) AF: 0.00450 AC: 388 AN: 86250

European-Finnish (FIN) AF: 0.0309 AC: 1648 AN: 53386

Middle Eastern (MID) AF: 0.0179 AC: 103 AN: 5764

European-Non Finnish (NFE) AF: 0.0315 AC: 35010 AN: 1111714

Other (OTH) AF: 0.0252 AC: 1519 AN: 60370

GnomAD4 genome AF: 0.0213 AC: 3236 AN: 152218 Hom.: 44 Cov.: 31 AF XY: 0.0202 AC XY: 1504 AN XY: 74412

African (AFR) AF: 0.00623 AC: 259 AN: 41546

American (AMR) AF: 0.0190 AC: 291 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0259 AC: 90 AN: 3472

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5170

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4822

European-Finnish (FIN) AF: 0.0290 AC: 307 AN: 10592

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0324 AC: 2206 AN: 68016

Other (OTH) AF: 0.0199 AC: 42 AN: 2110

Alfa AF: 0.0284 Hom.: 245

Bravo AF: 0.0204

TwinsUK AF: 0.0286 AC: 106

ALSPAC AF: 0.0322 AC: 124

ESP6500AA AF: 0.00714 AC: 29

ESP6500EA AF: 0.0302 AC: 254

ExAC AF: 0.0238 AC: 2880

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Congenital myasthenic syndrome 9 (1)
-	-	1	Fetal akinesia deformation sequence 1;C4225368:Congenital myasthenic syndrome 9 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	12
DANN	Benign	0.85
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.026	N
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L
PhyloP100		0.21
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.11
Sift	Benign	0.23	T
Sift4G	Benign	0.12	T
Polyphen		0.16	B
Vest4		0.092
MPC		0.19
ClinPred		0.0073	T
GERP RS		-7.1
PromoterAI		0.0018	Neutral
Varity_R		0.039
gMVP		0.46
Mutation Taster		=298/2	polymorphism (auto)

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: rs35142681; hg19: chr9-113449489; COSMIC: COSV105049818; COSMIC: COSV105049818;