rs551423795

Variant names:

• chr9-110687218-A-G
• rs551423795
• NM_005592.4:c.308A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_005592.4(MUSK):​c.308A>G​(p.Asn103Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,613,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. N103N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: MUSK NM_005592.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 8.52
• Publications: 6 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-110687218-A-G is Pathogenic according to our data. Variant chr9-110687218-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 218372.
• BP4: Computational evidence support a benign effect (MetaRNN=0.4228711). . Strength limited to SUPPORTING due to the PP5.

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.308A>G	p.Asn103Ser	missense	Exon 3 of 15	NP_005583.1	O15146-1
	MUSK	NM_001166280.2		c.308A>G	p.Asn103Ser	missense	Exon 3 of 14	NP_001159752.1	O15146-2
	MUSK	NM_001166281.2		c.308A>G	p.Asn103Ser	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.308A>G	p.Asn103Ser	missense	Exon 3 of 15	ENSP00000363571.4	O15146-1
	MUSK	ENST00000416899.7	TSL:5	c.308A>G	p.Asn103Ser	missense	Exon 3 of 14	ENSP00000393608.3	A0A087WSY1
	MUSK	ENST00000189978.10	TSL:5	c.308A>G	p.Asn103Ser	missense	Exon 3 of 14	ENSP00000189978.6	O15146-2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152134 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000241 AC: 6 AN: 249236 AF XY: 0.0000296

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1461614 Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15 AN XY: 727084

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.0000894 AC: 4 AN: 44718

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

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

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1111804

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152252 Hom.: 0 Cov.: 31 AF XY: 0.0000403 AC XY: 3 AN XY: 74438

African (AFR) AF: 0.0000241 AC: 1 AN: 41566

American (AMR) AF: 0.000131 AC: 2 AN: 15282

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000230 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000331 AC: 4

EpiCase AF: 0.00

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 9 (1)
1	-	-	Fetal akinesia deformation sequence 1 (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	Uncertain	0.35
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.15	T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.33	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		8.5
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.27
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.031	D
Polyphen		1.0	D
Vest4		0.98
MVP		0.74
MPC		0.35
ClinPred		0.78	D
GERP RS		6.0
PromoterAI		-0.027	Neutral
Varity_R		0.44
gMVP		0.88
Mutation Taster		=164/136	disease causing (ClinVar)

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: rs551423795; hg19: chr9-113449498;