1-1046562-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_198576.4(AGRN):c.3077C>A(p.Thr1026Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00596 in 1,609,174 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0070 ( 14 hom., cov: 33)

Exomes 𝑓: 0.0058 ( 52 hom. )

Consequence

AGRN
NM_198576.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.30

Publications

9 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: STRONG Submitted by: PanelApp Australia, 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=0.0045595467).

BP6

Variant 1-1046562-C-A is Benign according to our data. Variant chr1-1046562-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 263179.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 = 0.00703 (1070/152272) while in subpopulation EAS AF = 0.0325 (168/5172). AF 95% confidence interval is 0.0285. There are 14 homozygotes in GnomAd4. There are 606 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4 link	c.3077C>A	p.Thr1026Asn	missense_variant	Exon 18 of 36	ENST00000379370.7	NP_940978.2	O00468-6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7 link	c.3077C>A	p.Thr1026Asn	missense_variant	Exon 18 of 36	1	NM_198576.4	ENSP00000368678.2		O00468-6

Frequencies

GnomAD3 genomes

AF:

0.00703

AC:

1070

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.00589

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.0326

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.0285

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00626

Gnomad OTH

AF:

0.00574

GnomAD2 exomes

AF:

0.00811

AC:

1972

AN:

243190

AF XY:

0.00790

show subpopulations

Gnomad AFR exome

AF:

0.000579

Gnomad AMR exome

AF:

0.00108

Gnomad ASJ exome

AF:

0.00131

Gnomad EAS exome

AF:

0.0330

Gnomad FIN exome

AF:

0.0267

Gnomad NFE exome

AF:

0.00621

Gnomad OTH exome

AF:

0.00920

GnomAD4 exome

AF:

0.00584

AC:

8514

AN:

1456902

Hom.:

Cov.:

AF XY:

0.00583

AC XY:

4223

AN XY:

724898

show subpopulations

African (AFR)

AF:

0.000538

AC:

AN:

33448

American (AMR)

AF:

0.00164

AC:

AN:

44570

Ashkenazi Jewish (ASJ)

AF:

0.00207

AC:

AN:

26082

East Asian (EAS)

AF:

0.0293

AC:

1163

AN:

39662

South Asian (SAS)

AF:

0.00247

AC:

213

AN:

86208

European-Finnish (FIN)

AF:

0.0263

AC:

1303

AN:

49562

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00479

AC:

5327

AN:

1111332

Other (OTH)

AF:

0.00589

AC:

355

AN:

60270

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

546

1093

1639

2186

2732

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

188

376

564

752

940

<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:

0.00703

AC:

1070

AN:

152272

Hom.:

Cov.:

AF XY:

0.00814

AC XY:

606

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.000722

AC:

AN:

41552

American (AMR)

AF:

0.00588

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

3472

East Asian (EAS)

AF:

0.0325

AC:

168

AN:

5172

South Asian (SAS)

AF:

0.00352

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0285

AC:

303

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00626

AC:

426

AN:

68004

Other (OTH)

AF:

0.00568

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

102

152

203

254

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00624

Hom.:

Bravo

AF:

0.00511

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00419

AC:

ExAC

AF:

0.00844

AC:

1018

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.00431

EpiControl

AF:

0.00528

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 23, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Congenital myasthenic syndrome 8

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.95

Eigen

Benign

0.12

Eigen_PC

Benign

0.012

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.82

T;T

MetaRNN

Benign

0.0046

T;T

MetaSVM

Benign

-0.76

MutationAssessor

Uncertain

2.1

M;.

PhyloP100

1.3

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.6

N;.

REVEL

Benign

0.17

Sift

Benign

0.29

T;.

Sift4G

Benign

0.088

T;T

Vest4

0.27

MVP

0.84

MPC

0.29

ClinPred

0.012

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.21

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over