Genetic Variant AGRN:p.Pro1240Leu (chr1-1047863-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_198576.4(AGRN):c.3719C>T(p.Pro1240Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00238 in 1,605,870 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1240Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0021 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0024 ( 9 hom. )

Consequence

AGRN
NM_198576.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 4.04

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04960853).

BP6

Variant 1-1047863-C-T is Benign according to our data. Variant chr1-1047863-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 263182.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-1047863-C-T is described in Lovd as [Benign].

BS2

High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4 link	c.3719C>T	p.Pro1240Leu	missense_variant	Exon 22 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.3719C>T	p.Pro1240Leu	missense_variant	Exon 22 of 36	1	NM_198576.4	ENSP00000368678.2		O00468-6

Frequencies

GnomAD3 genomes

AF:

0.00214

AC:

325

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00288

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00226

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00346

Gnomad OTH

AF:

0.000959

GnomAD3 exomes

AF:

0.00191

AC:

434

AN:

227228

Hom.:

AF XY:

0.00190

AC XY:

237

AN XY:

124910

show subpopulations

Gnomad AFR exome

AF:

0.000225

Gnomad AMR exome

AF:

0.00112

Gnomad ASJ exome

AF:

0.00296

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00242

Gnomad NFE exome

AF:

0.00306

Gnomad OTH exome

AF:

0.00250

GnomAD4 exome

AF:

0.00240

AC:

3494

AN:

1453648

Hom.:

Cov.:

AF XY:

0.00235

AC XY:

1699

AN XY:

722568

show subpopulations

Gnomad4 AFR exome

AF:

0.000390

Gnomad4 AMR exome

AF:

0.00130

Gnomad4 ASJ exome

AF:

0.00316

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000235

Gnomad4 FIN exome

AF:

0.00311

Gnomad4 NFE exome

AF:

0.00275

Gnomad4 OTH exome

AF:

0.00213

GnomAD4 genome

AF:

0.00214

AC:

325

AN:

152222

Hom.:

Cov.:

AF XY:

0.00206

AC XY:

153

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.00288

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00226

Gnomad4 NFE

AF:

0.00346

Gnomad4 OTH

AF:

0.000949

Alfa

AF:

0.00269

Hom.:

Bravo

AF:

0.00167

ESP6500AA

AF:

0.000458

AC:

ESP6500EA

AF:

0.00293

AC:

ExAC

AF:

0.00205

AC:

246

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

AGRN-related disorder

Benign:1

Aug 25, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely 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: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

DANN

Uncertain

1.0

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

D;D

M_CAP

Pathogenic

0.36

MetaRNN

Benign

0.050

T;T

MetaSVM

Uncertain

-0.14

MutationAssessor

Uncertain

2.3

M;.

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-5.2

D;.

REVEL

Uncertain

0.55

Sift

Benign

0.13

T;.

Sift4G

Pathogenic

0.0

D;D

Vest4

0.73

MVP

0.86

MPC

0.57

ClinPred

0.064

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.75

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over