rs9697293

Variant names:

Variant summary

Our verdict is Benign. Variant got -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. 14/18 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

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 263173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1045751-A-G is described in Lovd as [Benign].

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4 link	c.2555A>G	p.Gln852Arg	missense_variant	Exon 15 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.2555A>G	p.Gln852Arg	missense_variant	Exon 15 of 36	1	NM_198576.4	ENSP00000368678.2		O00468-6

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

GnomAD3 exomes

AF:

0.0123

AC:

3075

AN:

250798

Hom.:

AF XY:

0.0113

AC XY:

1534

AN XY:

135782

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 SAS exome

AF:

0.00853

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

Gnomad4 AFR exome

AF:

0.0737

Gnomad4 AMR exome

AF:

0.00675

Gnomad4 ASJ exome

AF:

0.00551

Gnomad4 EAS exome

AF:

0.0303

Gnomad4 SAS exome

AF:

0.00936

Gnomad4 FIN exome

AF:

0.0182

Gnomad4 NFE exome

AF:

0.00211

Gnomad4 OTH exome

AF:

0.0101

GnomAD4 genome

AF:

0.0247

AC:

3763

AN:

152250

Hom.:

108

Cov.:

AF XY:

0.0253

AC XY:

1883

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.0713

Gnomad4 AMR

AF:

0.0115

Gnomad4 ASJ

AF:

0.00375

Gnomad4 EAS

AF:

0.0315

Gnomad4 SAS

AF:

0.0102

Gnomad4 FIN

AF:

0.0190

Gnomad4 NFE

AF:

0.00247

Gnomad4 OTH

AF:

0.0137

Alfa

AF:

0.00800

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

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 31, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.54

DANN

Benign

0.64

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.63

T;T

MetaRNN

Benign

0.0080

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.070

N;.

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.39

N;.

REVEL

Benign

0.036

Sift

Benign

0.37

T;.

Sift4G

Benign

0.84

T;T

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

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

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