rs527639453

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_198576.4(AGRN):c.6119G>A(p.Arg2040Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000187 in 1,548,844 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00019 ( 1 hom. )

Consequence

AGRN
NM_198576.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.02

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:

ENSG00000242590 (HGNC:):

ENSG00000242590 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.015693218).

BP6

Variant 1-1054962-G-A is Benign according to our data. Variant chr1-1054962-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 474168.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4 link	c.6119G>A	p.Arg2040Gln	missense_variant	Exon 36 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.6119G>A	p.Arg2040Gln	missense_variant	Exon 36 of 36	1	NM_198576.4	ENSP00000368678.2		O00468-6

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00352

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000447

AC:

AN:

152046

Hom.:

AF XY:

0.000517

AC XY:

AN XY:

81204

show subpopulations

Gnomad AFR exome

AF:

0.000126

Gnomad AMR exome

AF:

0.0000403

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000899

Gnomad SAS exome

AF:

0.00281

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000171

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000193

AC:

269

AN:

1396526

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

185

AN XY:

688984

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000558

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00292

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000250

Gnomad4 OTH exome

AF:

0.000155

GnomAD4 genome

AF:

0.000131

AC:

AN:

152318

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00332

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000153

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.000340

AC:

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Feb 19, 2025

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Congenital myasthenic syndrome 8

Benign:1

Aug 31, 2024

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

-0.47

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Uncertain

0.97

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.98

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.78

T;T

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.016

T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.6

N;.

REVEL

Benign

0.16

Sift

Benign

0.31

T;.

Sift4G

Benign

0.35

T;T

Vest4

0.072

MutPred

0.74

Loss of methylation at R2040 (P = 0.2257);.;

MVP

0.77

MPC

0.14

ClinPred

0.028

GERP RS

-0.35

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.24

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