rs55980069

Variant names:

• chr9-110695442-T-C
• rs55980069
• NM_005592.4:c.398T>C

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.398T>C​(p.Ile133Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00592 in 1,539,768 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I133V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0061 (38 hom.)
• Consequence: MUSK NM_005592.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.74
• Publications: 5 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=0.006833166).
• BP6: Variant 9-110695442-T-C is Benign according to our data. Variant chr9-110695442-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 197256.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 = 0.00393 (599/152300) while in subpopulation NFE AF = 0.0061 (415/68006). AF 95% confidence interval is 0.00562. There are 0 homozygotes in GnomAd4. There are 298 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 38 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.398T>C	p.Ile133Thr	missense	Exon 4 of 15	NP_005583.1	O15146-1
	MUSK	NM_001166280.2		c.398T>C	p.Ile133Thr	missense	Exon 4 of 14	NP_001159752.1	O15146-2
	MUSK	NM_001166281.2		c.398T>C	p.Ile133Thr	missense	Exon 4 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.398T>C	p.Ile133Thr	missense	Exon 4 of 15	ENSP00000363571.4	O15146-1
	MUSK	ENST00000416899.7	TSL:5	c.398T>C	p.Ile133Thr	missense	Exon 4 of 14	ENSP00000393608.3	A0A087WSY1
	MUSK	ENST00000189978.10	TSL:5	c.398T>C	p.Ile133Thr	missense	Exon 4 of 14	ENSP00000189978.6	O15146-2

Frequencies

GnomAD3 genomes AF: 0.00394 AC: 599 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00610

Gnomad OTH AF: 0.00764

GnomAD2 exomes AF: 0.00451 AC: 796 AN: 176308 AF XY: 0.00443

Gnomad AFR exome AF: 0.00132

Gnomad AMR exome AF: 0.00260

Gnomad ASJ exome AF: 0.0109

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00209

Gnomad NFE exome AF: 0.00673

Gnomad OTH exome AF: 0.00553

GnomAD4 exome AF: 0.00613 AC: 8511 AN: 1387468 Hom.: 38 Cov.: 27 AF XY: 0.00600 AC XY: 4122 AN XY: 686668

African (AFR) AF: 0.00104 AC: 33 AN: 31828

American (AMR) AF: 0.00321 AC: 119 AN: 37026

Ashkenazi Jewish (ASJ) AF: 0.0110 AC: 276 AN: 25128

East Asian (EAS) AF: 0.0000267 AC: 1 AN: 37424

South Asian (SAS) AF: 0.00299 AC: 232 AN: 77716

European-Finnish (FIN) AF: 0.00207 AC: 105 AN: 50622

Middle Eastern (MID) AF: 0.00388 AC: 22 AN: 5666

European-Non Finnish (NFE) AF: 0.00694 AC: 7389 AN: 1064228

Other (OTH) AF: 0.00578 AC: 334 AN: 57830

GnomAD4 genome AF: 0.00393 AC: 599 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.00400 AC XY: 298 AN XY: 74482

African (AFR) AF: 0.00111 AC: 46 AN: 41578

American (AMR) AF: 0.00268 AC: 41 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 39 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4828

European-Finnish (FIN) AF: 0.00245 AC: 26 AN: 10614

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00610 AC: 415 AN: 68006

Other (OTH) AF: 0.00756 AC: 16 AN: 2116

Alfa AF: 0.00559 Hom.: 15

Bravo AF: 0.00403

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.00110 AC: 4

ESP6500EA AF: 0.00690 AC: 56

ExAC AF: 0.00323 AC: 384

Asia WGS AF: 0.00115 AC: 5 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Congenital myasthenic syndrome 9 (1)
-	-	1	Fetal akinesia deformation sequence 1;C4225368:Congenital myasthenic syndrome 9 (1)
-	-	1	MUSK-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	20
DANN	Benign	0.91
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0068	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.53	N
PhyloP100		2.7
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.042
Sift	Benign	0.061	T
Sift4G	Benign	0.62	T
Polyphen		0.0060	B
Vest4		0.35
MVP		0.36
MPC		0.21
ClinPred		0.019	T
GERP RS		1.2
Varity_R		0.071
gMVP		0.67
Mutation Taster		=93/7	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: rs55980069; hg19: chr9-113457722;