9-110695537-G-A

Variant names:

• chr9-110695537-G-A
• rs187497836
• NM_005592.4:c.486+7G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005592.4(MUSK):​c.486+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000431 in 1,390,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: MUSK NM_005592.4 splice_region, intron
• Scores: Splicing: ADA: 0.00007647
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.674
• 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), 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUSK	NM_005592.4	c.486+7G>A		splice_region_variant, intron_variant	Intron 4 of 14	ENST00000374448.9	NP_005583.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUSK	ENST00000374448.9	c.486+7G>A		splice_region_variant, intron_variant	Intron 4 of 14	5	NM_005592.4	ENSP00000363571.4
MUSK	ENST00000416899.7	c.486+7G>A		splice_region_variant, intron_variant	Intron 4 of 13	5		ENSP00000393608.3
MUSK	ENST00000189978.10	c.486+7G>A		splice_region_variant, intron_variant	Intron 4 of 13	5		ENSP00000189978.6
MUSK	ENST00000374439.1	c.180+7G>A		splice_region_variant, intron_variant	Intron 2 of 3	5		ENSP00000363562.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000431 AC: 6 AN: 1390594 Hom.: 0 Cov.: 28 AF XY: 0.00000437 AC XY: 3 AN XY: 686534

African (AFR) AF: 0.00 AC: 0 AN: 31288

American (AMR) AF: 0.00 AC: 0 AN: 34364

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24930

East Asian (EAS) AF: 0.00 AC: 0 AN: 36266

South Asian (SAS) AF: 0.00 AC: 0 AN: 76130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5680

European-Non Finnish (NFE) AF: 0.00000559 AC: 6 AN: 1073928

Other (OTH) AF: 0.00 AC: 0 AN: 57884

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	7.4
DANN	Benign	0.41
PhyloP100		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000076
dbscSNV1_RF	Benign	0.074
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: rs187497836; hg19: chr9-113457817;