9-110800369-A-G

Variant names:

• chr9-110800369-A-G
• rs55963442
• NM_005592.4:c.1991A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005592.4(MUSK):​c.1991A>G​(p.Asn664Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.011 in 1,613,820 control chromosomes in the GnomAD database, including 162 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (13 hom., cov: 32)
  • Exomes 𝑓: 0.011 (149 hom.)
• Consequence: MUSK NM_005592.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 9.32
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012486756).
• BP6: Variant 9-110800369-A-G is Benign according to our data. Variant chr9-110800369-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00809 (1231/152114) while in subpopulation EAS AF = 0.0141 (73/5166). AF 95% confidence interval is 0.0116. There are 13 homozygotes in GnomAd4. There are 554 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 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.1991A>G	p.Asn664Ser	missense	Exon 15 of 15	NP_005583.1	O15146-1
	MUSK	NM_001166280.2		c.1733A>G	p.Asn578Ser	missense	Exon 14 of 14	NP_001159752.1	O15146-2
	MUSK	NM_001166281.2		c.1703A>G	p.Asn568Ser	missense	Exon 13 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.1991A>G	p.Asn664Ser	missense	Exon 15 of 15	ENSP00000363571.4	O15146-1
	MUSK	ENST00000416899.7	TSL:5	c.1967A>G	p.Asn656Ser	missense	Exon 14 of 14	ENSP00000393608.3	A0A087WSY1
	MUSK	ENST00000189978.10	TSL:5	c.1733A>G	p.Asn578Ser	missense	Exon 14 of 14	ENSP00000189978.6	O15146-2

Frequencies

GnomAD3 genomes AF: 0.00811 AC: 1232 AN: 151996 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00213

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00786

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.0141

Gnomad SAS AF: 0.00977

Gnomad FIN AF: 0.00368

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0123

Gnomad OTH AF: 0.00288

GnomAD2 exomes AF: 0.00833 AC: 2076 AN: 249104 AF XY: 0.00867

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00446

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.00178

Gnomad FIN exome AF: 0.00418

Gnomad NFE exome AF: 0.0125

Gnomad OTH exome AF: 0.00860

GnomAD4 exome AF: 0.0113 AC: 16491 AN: 1461706 Hom.: 149 Cov.: 32 AF XY: 0.0112 AC XY: 8165 AN XY: 727134

African (AFR) AF: 0.00149 AC: 50 AN: 33480

American (AMR) AF: 0.00429 AC: 192 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00237 AC: 62 AN: 26134

East Asian (EAS) AF: 0.0280 AC: 1113 AN: 39700

South Asian (SAS) AF: 0.00924 AC: 797 AN: 86258

European-Finnish (FIN) AF: 0.00489 AC: 261 AN: 53402

Middle Eastern (MID) AF: 0.00451 AC: 26 AN: 5768

European-Non Finnish (NFE) AF: 0.0121 AC: 13427 AN: 1111866

Other (OTH) AF: 0.00933 AC: 563 AN: 60374

GnomAD4 genome AF: 0.00809 AC: 1231 AN: 152114 Hom.: 13 Cov.: 32 AF XY: 0.00745 AC XY: 554 AN XY: 74378

African (AFR) AF: 0.00212 AC: 88 AN: 41504

American (AMR) AF: 0.00785 AC: 120 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3466

East Asian (EAS) AF: 0.0141 AC: 73 AN: 5166

South Asian (SAS) AF: 0.00957 AC: 46 AN: 4806

European-Finnish (FIN) AF: 0.00368 AC: 39 AN: 10600

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0123 AC: 836 AN: 67976

Other (OTH) AF: 0.00285 AC: 6 AN: 2106

Alfa AF: 0.00987 Hom.: 17

Bravo AF: 0.00759

TwinsUK AF: 0.0124 AC: 46

ALSPAC AF: 0.0143 AC: 55

ESP6500AA AF: 0.00423 AC: 18

ESP6500EA AF: 0.0130 AC: 110

ExAC AF: 0.00858 AC: 1039

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0106

EpiControl AF: 0.0119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Fetal akinesia deformation sequence 1;C4225368:Congenital myasthenic syndrome 9 (2)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Congenital myasthenic syndrome 9 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	0.74	N
PhyloP100		9.3
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.44
Sift	Benign	0.081	T
Sift4G	Benign	0.077	T
Polyphen		0.47	P
Vest4		0.69
MVP		0.84
MPC		0.54
ClinPred		0.026	T
GERP RS		5.2
Varity_R		0.38
gMVP		0.46
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs55963442; hg19: chr9-113562649; COSMIC: COSV99079049;