9-110775792-T-C

Variant names:

• chr9-110775792-T-C
• rs79843573
• NM_005592.4:c.1189T>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.1189T>C​(p.Tyr397His) variant causes a missense change. The variant allele was found at a frequency of 0.00141 in 1,613,726 control chromosomes in the GnomAD database, including 21 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0061 (11 hom., cov: 32)
  • Exomes 𝑓: 0.00092 (10 hom.)
• Consequence: MUSK NM_005592.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.34
• Publications: 4 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

LOC107987115 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.012265563).
• BP6: Variant 9-110775792-T-C is Benign according to our data. Variant chr9-110775792-T-C is described in ClinVar as Benign. ClinVar VariationId is 259799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00608 (926/152262) while in subpopulation AFR AF = 0.0205 (850/41540). AF 95% confidence interval is 0.0193. There are 11 homozygotes in GnomAd4. There are 421 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 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.1189T>C	p.Tyr397His	missense	Exon 10 of 15	NP_005583.1	O15146-1
	MUSK	NM_001166280.2		c.955T>C	p.Tyr319His	missense	Exon 10 of 14	NP_001159752.1	O15146-2
	MUSK	NM_001166281.2		c.925T>C	p.Tyr309His	missense	Exon 9 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.1189T>C	p.Tyr397His	missense	Exon 10 of 15	ENSP00000363571.4	O15146-1
	MUSK	ENST00000416899.7	TSL:5	c.1189T>C	p.Tyr397His	missense	Exon 10 of 14	ENSP00000393608.3	A0A087WSY1
	MUSK	ENST00000189978.10	TSL:5	c.955T>C	p.Tyr319His	missense	Exon 10 of 14	ENSP00000189978.6	O15146-2

Frequencies

GnomAD3 genomes AF: 0.00610 AC: 928 AN: 152144 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0205

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00161 AC: 402 AN: 249148 AF XY: 0.00123

Gnomad AFR exome AF: 0.0189

Gnomad AMR exome AF: 0.00180

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000328

Gnomad OTH exome AF: 0.00182

GnomAD4 exome AF: 0.000918 AC: 1342 AN: 1461464 Hom.: 10 Cov.: 30 AF XY: 0.000865 AC XY: 629 AN XY: 727032

African (AFR) AF: 0.0201 AC: 673 AN: 33460

American (AMR) AF: 0.00183 AC: 82 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5764

European-Non Finnish (NFE) AF: 0.000396 AC: 440 AN: 1111690

Other (OTH) AF: 0.00224 AC: 135 AN: 60372

GnomAD4 genome AF: 0.00608 AC: 926 AN: 152262 Hom.: 11 Cov.: 32 AF XY: 0.00565 AC XY: 421 AN XY: 74448

African (AFR) AF: 0.0205 AC: 850 AN: 41540

American (AMR) AF: 0.00255 AC: 39 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68030

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00274 Hom.: 6

Bravo AF: 0.00668

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0156 AC: 58

ESP6500EA AF: 0.000244 AC: 2

ExAC AF: 0.00171 AC: 207

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	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	Pathogenic	0.78
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.068	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.81	N
PhyloP100		4.3
PrimateAI	Benign	0.47	T
PROVEAN	Benign	1.6	N
REVEL	Benign	0.26
Sift	Benign	0.19	T
Sift4G	Benign	0.69	T
Polyphen		0.0010	B
Vest4		0.085
MVP		0.61
MPC		0.23
ClinPred		0.038	T
GERP RS		4.3
Varity_R		0.057
gMVP		0.74
Mutation Taster		=97/3	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: rs79843573; hg19: chr9-113538072;