rs200750233

Variant names:

• chr9-110695530-G-C
• rs200750233
• NM_005592.4:c.486G>C

Your query was ambiguous. Multiple possible variants found:

• chr9-110695530-G-C
• chr9-110695530-G-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PP3_Moderate BP6 BS1

The NM_005592.4(MUSK):​c.486G>C​(p.Arg162Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000203 in 1,549,130 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R162R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: MUSK NM_005592.4 missense, splice_region
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 4.73
• Publications: 1 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 -3 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 9-110695530-G-C is Benign according to our data. Variant chr9-110695530-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 197258.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000289 (44/152160) while in subpopulation AFR AF = 0.000361 (15/41514). AF 95% confidence interval is 0.000222. There are 0 homozygotes in GnomAd4. There are 18 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.486G>C	p.Arg162Ser	missense splice_region	Exon 4 of 15	NP_005583.1
	MUSK	NM_001166280.2		c.486G>C	p.Arg162Ser	missense splice_region	Exon 4 of 14	NP_001159752.1
	MUSK	NM_001166281.2		c.486G>C	p.Arg162Ser	missense splice_region	Exon 4 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.486G>C	p.Arg162Ser	missense splice_region	Exon 4 of 15	ENSP00000363571.4
	MUSK	ENST00000416899.7	TSL:5	c.486G>C	p.Arg162Ser	missense splice_region	Exon 4 of 14	ENSP00000393608.3
	MUSK	ENST00000189978.10	TSL:5	c.486G>C	p.Arg162Ser	missense splice_region	Exon 4 of 14	ENSP00000189978.6

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152042 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000287 AC: 48 AN: 167072 AF XY: 0.000283

Gnomad AFR exome AF: 0.000206

Gnomad AMR exome AF: 0.000504

Gnomad ASJ exome AF: 0.00211

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000228

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000193 AC: 270 AN: 1396970 Hom.: 0 Cov.: 28 AF XY: 0.000207 AC XY: 143 AN XY: 689872

African (AFR) AF: 0.000285 AC: 9 AN: 31568

American (AMR) AF: 0.000397 AC: 14 AN: 35304

Ashkenazi Jewish (ASJ) AF: 0.00299 AC: 75 AN: 25044

East Asian (EAS) AF: 0.00 AC: 0 AN: 36658

South Asian (SAS) AF: 0.00 AC: 0 AN: 76648

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50382

Middle Eastern (MID) AF: 0.00176 AC: 10 AN: 5690

European-Non Finnish (NFE) AF: 0.000128 AC: 138 AN: 1077546

Other (OTH) AF: 0.000413 AC: 24 AN: 58130

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152160 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74402

African (AFR) AF: 0.000361 AC: 15 AN: 41514

American (AMR) AF: 0.000327 AC: 5 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

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

European-Non Finnish (NFE) AF: 0.000177 AC: 12 AN: 67982

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000309 Hom.: 0

Bravo AF: 0.000344

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000276 AC: 1

ESP6500EA AF: 0.000247 AC: 2

ExAC AF: 0.000188 AC: 22

Asia WGS AF: 0.000578 AC: 2 AN: 3472

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Congenital myasthenic syndrome 9 (2)
-	-	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	0.52
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.46	N
PhyloP100		4.7
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.18
Sift	Benign	0.064	T
Sift4G	Uncertain	0.033	D
Polyphen		0.42	B
Vest4		0.43
MutPred		0.56		Gain of disorder (P = 0.07)
MVP		0.75
MPC		0.23
ClinPred		0.021	T
GERP RS		6.0
Varity_R		0.27
gMVP		0.50
Mutation Taster		=62/38	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.010		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: rs200750233; hg19: chr9-113457810;