rs9697293

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_198576.4(AGRN):c.2555A>G(p.Gln852Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00785 in 1,613,344 control chromosomes in the GnomAD database, including 260 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 108 hom., cov: 33)

Exomes 𝑓: 0.0061 ( 152 hom. )

Consequence

AGRN
NM_198576.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.151

Publications

11 publications found

Variant links:

Genes affected

AGRN (HGNC:329): (agrin) This gene encodes one of several proteins that are critical in the development of the neuromuscular junction (NMJ), as identified in mouse knock-out studies. The encoded protein contains several laminin G, Kazal type serine protease inhibitor, and epidermal growth factor domains. Additional post-translational modifications occur to add glycosaminoglycans and disulfide bonds. In one family with congenital myasthenic syndrome affecting limb-girdle muscles, a mutation in this gene was found. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2015]

AGRN Gene-Disease associations (from GenCC):

congenital myasthenic syndrome 8
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
presynaptic congenital myasthenic syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
postsynaptic congenital myasthenic syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

AGRN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007983774).

BP6

Variant 1-1045751-A-G is Benign according to our data. Variant chr1-1045751-A-G is described in ClinVar as Benign. ClinVar VariationId is 263173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0692 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198576.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AGRN	NM_198576.4	MANE Select	c.2555A>G	p.Gln852Arg	missense	Exon 15 of 36	NP_940978.2
AGRN	NM_001305275.2		c.2555A>G	p.Gln852Arg	missense	Exon 15 of 39	NP_001292204.1	O00468-1
AGRN	NM_001364727.2		c.2240A>G	p.Gln747Arg	missense	Exon 14 of 36	NP_001351656.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AGRN	ENST00000379370.7	TSL:1 MANE Select	c.2555A>G	p.Gln852Arg	missense	Exon 15 of 36	ENSP00000368678.2	O00468-6
AGRN	ENST00000651234.1		c.2240A>G	p.Gln747Arg	missense	Exon 14 of 38	ENSP00000499046.1	A0A494C1I6
AGRN	ENST00000652369.2		c.2240A>G	p.Gln747Arg	missense	Exon 14 of 35	ENSP00000498543.1	A0A494C0G5

Frequencies

GnomAD3 genomes

AF:

0.0246

AC:

3749

AN:

152132

Hom.:

106

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0712

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0115

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.0316

Gnomad SAS

AF:

0.00995

Gnomad FIN

AF:

0.0190

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00247

Gnomad OTH

AF:

0.0138

GnomAD2 exomes

AF:

0.0123

AC:

3075

AN:

250798

AF XY:

0.0113

show subpopulations

Gnomad AFR exome

AF:

0.0733

Gnomad AMR exome

AF:

0.00642

Gnomad ASJ exome

AF:

0.00587

Gnomad EAS exome

AF:

0.0279

Gnomad FIN exome

AF:

0.0197

Gnomad NFE exome

AF:

0.00306

Gnomad OTH exome

AF:

0.00946

GnomAD4 exome

AF:

0.00609

AC:

8902

AN:

1461094

Hom.:

152

Cov.:

AF XY:

0.00599

AC XY:

4351

AN XY:

726876

show subpopulations

African (AFR)

AF:

0.0737

AC:

2468

AN:

33476

American (AMR)

AF:

0.00675

AC:

302

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00551

AC:

144

AN:

26128

East Asian (EAS)

AF:

0.0303

AC:

1204

AN:

39694

South Asian (SAS)

AF:

0.00936

AC:

807

AN:

86258

European-Finnish (FIN)

AF:

0.0182

AC:

962

AN:

52734

Middle Eastern (MID)

AF:

0.0107

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00211

AC:

2344

AN:

1111938

Other (OTH)

AF:

0.0101

AC:

609

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

643

1286

1928

2571

3214

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

160

320

480

640

800

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0247

AC:

3763

AN:

152250

Hom.:

108

Cov.:

AF XY:

0.0253

AC XY:

1883

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.0713

AC:

2962

AN:

41538

American (AMR)

AF:

0.0115

AC:

176

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00375

AC:

AN:

3470

East Asian (EAS)

AF:

0.0315

AC:

163

AN:

5172

South Asian (SAS)

AF:

0.0102

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0190

AC:

202

AN:

10608

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00247

AC:

168

AN:

68012

Other (OTH)

AF:

0.0137

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

181

363

544

726

907

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0122

Hom.:

Bravo

AF:

0.0255

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.0679

AC:

299

ESP6500EA

AF:

0.00233

AC:

ExAC

AF:

0.0137

AC:

1663

Asia WGS

AF:

0.0260

AC:

AN:

3478

EpiCase

AF:

0.00229

EpiControl

AF:

0.00279

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Congenital myasthenic syndrome 8 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.54

(source)

DANN

Benign

0.64

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.63

MetaRNN

Benign

0.0080

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.070

PhyloP100

-0.15

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.39

REVEL

Benign

0.036

Sift

Benign

0.37

Sift4G

Benign

0.84

Vest4

0.10

MPC

0.21

ClinPred

0.000018

GERP RS

-0.62

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.17

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over