rs56181115

Variant names:

• chr9-110687222-T-C
• rs56181115
• NM_005592.4:c.312T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_005592.4(MUSK):​c.312T>C​(p.Gly104Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000375 in 1,613,822 control chromosomes in the GnomAD database, including 7 homozygotes. 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 0.00027 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00039 (5 hom.)
• Consequence: MUSK NM_005592.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -1.78
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 9-110687222-T-C is Benign according to our data. Variant chr9-110687222-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 364601.
• BP7: Synonymous conserved (PhyloP=-1.78 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000269 (41/152192) while in subpopulation SAS AF = 0.00519 (25/4818). AF 95% confidence interval is 0.00361. There are 2 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.312T>C	p.Gly104Gly	synonymous	Exon 3 of 15	NP_005583.1	O15146-1
	MUSK	NM_001166280.2		c.312T>C	p.Gly104Gly	synonymous	Exon 3 of 14	NP_001159752.1	O15146-2
	MUSK	NM_001166281.2		c.312T>C	p.Gly104Gly	synonymous	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.312T>C	p.Gly104Gly	synonymous	Exon 3 of 15	ENSP00000363571.4	O15146-1
	MUSK	ENST00000416899.7	TSL:5	c.312T>C	p.Gly104Gly	synonymous	Exon 3 of 14	ENSP00000393608.3	A0A087WSY1
	MUSK	ENST00000189978.10	TSL:5	c.312T>C	p.Gly104Gly	synonymous	Exon 3 of 14	ENSP00000189978.6	O15146-2

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152072 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000706 AC: 176 AN: 249228 AF XY: 0.000947

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.000826

GnomAD4 exome AF: 0.000386 AC: 564 AN: 1461630 Hom.: 5 Cov.: 31 AF XY: 0.000530 AC XY: 385 AN XY: 727094

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.0000447 AC: 2 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00454 AC: 392 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5766

European-Non Finnish (NFE) AF: 0.000111 AC: 123 AN: 1111820

Other (OTH) AF: 0.000547 AC: 33 AN: 60368

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152192 Hom.: 2 Cov.: 31 AF XY: 0.000349 AC XY: 26 AN XY: 74402

African (AFR) AF: 0.0000481 AC: 2 AN: 41550

American (AMR) AF: 0.0000655 AC: 1 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00519 AC: 25 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

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

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 67994

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000229 Hom.: 1

Bravo AF: 0.000132

Asia WGS AF: 0.00231 AC: 10 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Congenital Myasthenic Syndrome, Recessive (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
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.9
DANN	Benign	0.64
PhyloP100		-1.8
PromoterAI		0.021	Neutral
Mutation Taster		=288/12	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: rs56181115; hg19: chr9-113449502;