chr1-1020239-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_198576.4(AGRN):c.67G>C(p.Val23Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00708 in 1,445,836 control chromosomes in the GnomAD database, including 111 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V23G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0067 ( 15 hom., cov: 33)

Exomes 𝑓: 0.0071 ( 96 hom. )

Consequence

AGRN
NM_198576.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 0.455

Publications

8 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018510222).

BP6

Variant 1-1020239-G-C is Benign according to our data. Variant chr1-1020239-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210112.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00673 (1021/151818) while in subpopulation SAS AF = 0.0311 (150/4830). AF 95% confidence interval is 0.027. There are 15 homozygotes in GnomAd4. There are 512 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 15 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4 link	c.67G>C	p.Val23Leu	missense_variant	Exon 1 of 36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7 link	c.67G>C	p.Val23Leu	missense_variant	Exon 1 of 36	1	NM_198576.4	ENSP00000368678.2
AGRN	ENST00000620552.4 link	c.-348G>C		5_prime_UTR_variant	Exon 1 of 39	5		ENSP00000484607.1

Frequencies

GnomAD3 genomes

AF:

0.00674

AC:

1022

AN:

151712

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00430

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00315

Gnomad ASJ

AF:

0.0185

Gnomad EAS

AF:

0.00502

Gnomad SAS

AF:

0.0308

Gnomad FIN

AF:

0.00364

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00735

Gnomad OTH

AF:

0.00913

GnomAD2 exomes

AF:

0.0119

AC:

905

AN:

75972

AF XY:

0.0147

show subpopulations

Gnomad AFR exome

AF:

0.00535

Gnomad AMR exome

AF:

0.00151

Gnomad ASJ exome

AF:

0.0164

Gnomad EAS exome

AF:

0.00305

Gnomad FIN exome

AF:

0.00371

Gnomad NFE exome

AF:

0.00672

Gnomad OTH exome

AF:

0.00779

GnomAD4 exome

AF:

0.00712

AC:

9212

AN:

1294018

Hom.:

Cov.:

AF XY:

0.00801

AC XY:

5109

AN XY:

637466

show subpopulations

African (AFR)

AF:

0.00445

AC:

117

AN:

26264

American (AMR)

AF:

0.00188

AC:

AN:

25044

Ashkenazi Jewish (ASJ)

AF:

0.0188

AC:

419

AN:

22344

East Asian (EAS)

AF:

0.000990

AC:

AN:

27282

South Asian (SAS)

AF:

0.0319

AC:

2212

AN:

69406

European-Finnish (FIN)

AF:

0.00543

AC:

193

AN:

35560

Middle Eastern (MID)

AF:

0.0164

AC:

AN:

3840

European-Non Finnish (NFE)

AF:

0.00549

AC:

5665

AN:

1031210

Other (OTH)

AF:

0.00884

AC:

469

AN:

53068

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

469

937

1406

1874

2343

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

224

448

672

896

1120

<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:

0.00673

AC:

1021

AN:

151818

Hom.:

Cov.:

AF XY:

0.00690

AC XY:

512

AN XY:

74248

show subpopulations

African (AFR)

AF:

0.00429

AC:

178

AN:

41494

American (AMR)

AF:

0.00315

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.0185

AC:

AN:

3468

East Asian (EAS)

AF:

0.00484

AC:

AN:

5168

South Asian (SAS)

AF:

0.0311

AC:

150

AN:

4830

European-Finnish (FIN)

AF:

0.00364

AC:

AN:

10444

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00735

AC:

499

AN:

67850

Other (OTH)

AF:

0.00856

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

104

155

207

259

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:

0.00180

Hom.:

Bravo

AF:

0.00583

ExAC

AF:

0.0136

AC:

314

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Oct 20, 2017

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 18, 2024

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria.

not specified

Uncertain:1

Sep 29, 2014

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

AGRN-related disorder

Benign:1

Apr 05, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Congenital myasthenic syndrome 8

Benign:1

Feb 03, 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

0.079

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.43

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0066

LIST_S2

Benign

0.50

MetaRNN

Benign

0.0019

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.14

PhyloP100

0.46

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-0.25

REVEL

Benign

0.040

Sift

Benign

0.63

Sift4G

Benign

0.19

Vest4

0.053

ClinPred

0.0045

GERP RS

1.0

PromoterAI

-0.016

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.19

Mutation Taster

=96/4

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