9-110734287-A-G

Variant names:

• chr9-110734287-A-G
• rs55826142
• NM_005592.4:c.665A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000374448.9(MUSK):​c.665A>G​(p.Asn222Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00178 in 1,613,064 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N222I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (3 hom.)
• Consequence: MUSK ENST00000374448.9 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5 O:1
• Conservation: PhyloP100: 6.76
• 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), 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04393962).
• BP6: Variant 9-110734287-A-G is Benign according to our data. Variant chr9-110734287-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 281408.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0011 (168/152104) while in subpopulation NFE AF = 0.00206 (140/67968). AF 95% confidence interval is 0.00178. There are 0 homozygotes in GnomAd4. There are 76 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000374448.9. 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.665A>G	p.Asn222Ser	missense	Exon 6 of 15	NP_005583.1
	MUSK	NM_001166280.2		c.695A>G	p.Asn232Ser	missense	Exon 7 of 14	NP_001159752.1
	MUSK	NM_001166281.2		c.665A>G	p.Asn222Ser	missense	Exon 6 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.665A>G	p.Asn222Ser	missense	Exon 6 of 15	ENSP00000363571.4
	MUSK	ENST00000416899.7	TSL:5	c.665A>G	p.Asn222Ser	missense	Exon 6 of 14	ENSP00000393608.3
	MUSK	ENST00000189978.10	TSL:5	c.695A>G	p.Asn232Ser	missense	Exon 7 of 14	ENSP00000189978.6

Frequencies

GnomAD3 genomes AF: 0.00111 AC: 168 AN: 151986 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00206

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000905 AC: 225 AN: 248698 AF XY: 0.000993

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.0000582

Gnomad ASJ exome AF: 0.00209

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00172

Gnomad OTH exome AF: 0.000498

GnomAD4 exome AF: 0.00185 AC: 2701 AN: 1460960 Hom.: 3 Cov.: 31 AF XY: 0.00183 AC XY: 1332 AN XY: 726750

African (AFR) AF: 0.0000299 AC: 1 AN: 33408

American (AMR) AF: 0.0000448 AC: 2 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 30 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.00 AC: 0 AN: 86210

European-Finnish (FIN) AF: 0.000243 AC: 13 AN: 53390

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

European-Non Finnish (NFE) AF: 0.00231 AC: 2570 AN: 1111452

Other (OTH) AF: 0.00141 AC: 85 AN: 60332

GnomAD4 genome AF: 0.00110 AC: 168 AN: 152104 Hom.: 0 Cov.: 32 AF XY: 0.00102 AC XY: 76 AN XY: 74344

African (AFR) AF: 0.000337 AC: 14 AN: 41524

American (AMR) AF: 0.000197 AC: 3 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.000472 AC: 5 AN: 10598

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

European-Non Finnish (NFE) AF: 0.00206 AC: 140 AN: 67968

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00157 Hom.: 0

Bravo AF: 0.00103

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000249 AC: 1

ESP6500EA AF: 0.00192 AC: 16

ExAC AF: 0.000877 AC: 106

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00164

EpiControl AF: 0.00131

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.65
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.079	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.044	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.080	N
PhyloP100		6.8
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.072
Sift	Benign	0.30	T
Sift4G	Benign	0.21	T
Polyphen		0.97	D
Vest4		0.58
MVP		0.22
MPC		0.62
ClinPred		0.061	T
GERP RS		5.2
Varity_R		0.11
gMVP		0.20
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs55826142; hg19: chr9-113496567;