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), 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 -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

Selected	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
	MUSK	NM_001166280.2		c.1733A>G	p.Asn578Ser	missense	Exon 14 of 14	NP_001159752.1
	MUSK	NM_001166281.2		c.1703A>G	p.Asn568Ser	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.1991A>G	p.Asn664Ser	missense	Exon 15 of 15	ENSP00000363571.4
	MUSK	ENST00000416899.7	TSL:5	c.1967A>G	p.Asn656Ser	missense	Exon 14 of 14	ENSP00000393608.3
	MUSK	ENST00000189978.10	TSL:5	c.1733A>G	p.Asn578Ser	missense	Exon 14 of 14	ENSP00000189978.6

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

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Jun 29, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Apr 07, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MUSK: BS1, BS2

Fetal akinesia deformation sequence 1;C4225368:Congenital myasthenic syndrome 9 Benign:2

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 02, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Congenital myasthenic syndrome 9 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.

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;