rs199811263

Variant names:

• chr9-110800329-A-C
• rs199811263
• NM_005592.4:c.1951A>C

Your query was ambiguous. Multiple possible variants found:

• chr9-110800329-A-C
• chr9-110800329-A-G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_005592.4(MUSK):​c.1951A>C​(p.Met651Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000208 in 1,610,786 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).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: MUSK NM_005592.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 5.12
• 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), 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.038600177).
• BP6: Variant 9-110800329-A-C is Benign according to our data. Variant chr9-110800329-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 570516.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000263 (40/152148) while in subpopulation NFE AF = 0.000368 (25/67994). AF 95% confidence interval is 0.000255. There are 0 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUSK	NM_005592.4	MANE Select	c.1951A>C	p.Met651Leu	missense	Exon 15 of 15	NP_005583.1
	MUSK	NM_001166280.2		c.1693A>C	p.Met565Leu	missense	Exon 14 of 14	NP_001159752.1
	MUSK	NM_001166281.2		c.1663A>C	p.Met555Leu	missense	Exon 13 of 13	NP_001159753.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUSK	ENST00000374448.9	TSL:5 MANE Select	c.1951A>C	p.Met651Leu	missense	Exon 15 of 15	ENSP00000363571.4
	MUSK	ENST00000416899.7	TSL:5	c.1927A>C	p.Met643Leu	missense	Exon 14 of 14	ENSP00000393608.3
	MUSK	ENST00000189978.10	TSL:5	c.1693A>C	p.Met565Leu	missense	Exon 14 of 14	ENSP00000189978.6

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152030 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000310 AC: 77 AN: 248074 AF XY: 0.000268

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00219

Gnomad NFE exome AF: 0.000223

Gnomad OTH exome AF: 0.000498

GnomAD4 exome AF: 0.000202 AC: 295 AN: 1458638 Hom.: 0 Cov.: 32 AF XY: 0.000214 AC XY: 155 AN XY: 724998

African (AFR) AF: 0.00 AC: 0 AN: 33414

American (AMR) AF: 0.0000224 AC: 1 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39592

South Asian (SAS) AF: 0.00 AC: 0 AN: 86150

European-Finnish (FIN) AF: 0.00264 AC: 141 AN: 53360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.000130 AC: 144 AN: 1109446

Other (OTH) AF: 0.000149 AC: 9 AN: 60212

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.000296 AC XY: 22 AN XY: 74402

African (AFR) AF: 0.0000482 AC: 2 AN: 41496

American (AMR) AF: 0.00 AC: 0 AN: 15292

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00123 AC: 13 AN: 10606

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

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 67994

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.000258 Hom.: 0

Bravo AF: 0.000125

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000237 AC: 2

ExAC AF: 0.000239 AC: 29

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Sep 15, 2023

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Fetal akinesia deformation sequence 1;C4225368:Congenital myasthenic syndrome 9 Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	-1.4	N
PhyloP100		5.1
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.26
Sift	Benign	0.24	T
Sift4G	Benign	0.56	T
Polyphen		0.92	P
Vest4		0.44
MutPred		0.47		Loss of methylation at K649 (P = 0.0859)
MVP		0.39
MPC		0.15
ClinPred		0.98	D
GERP RS		5.1
Varity_R		0.46
gMVP		0.57
Mutation Taster		=49/51	disease causing

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: rs199811263; hg19: chr9-113562609;