1-1020239-G-C

Position:

chr1-1020239-G-C

Variant summary

Our verdict is Benign. Variant got -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. 13/18 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

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 -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 id is 210112.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=1}.

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4 linkuse as main transcript	c.67G>C	p.Val23Leu	missense_variant	1/36	ENST00000379370.7	NP_940978.2	O00468-6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7 linkuse as main transcript	c.67G>C	p.Val23Leu	missense_variant	1/36	1	NM_198576.4	ENSP00000368678.2		O00468-6
AGRN	ENST00000620552 linkuse as main transcript	c.-348G>C		5_prime_UTR_variant	1/39	5		ENSP00000484607.1		A0A087X208

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

GnomAD3 exomes

AF:

0.0119

AC:

905

AN:

75972

Hom.:

AF XY:

0.0147

AC XY:

642

AN XY:

43528

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 SAS exome

AF:

0.0337

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

Gnomad4 AFR exome

AF:

0.00445

Gnomad4 AMR exome

AF:

0.00188

Gnomad4 ASJ exome

AF:

0.0188

Gnomad4 EAS exome

AF:

0.000990

Gnomad4 SAS exome

AF:

0.0319

Gnomad4 FIN exome

AF:

0.00543

Gnomad4 NFE exome

AF:

0.00549

Gnomad4 OTH exome

AF:

0.00884

GnomAD4 genome

AF:

0.00673

AC:

1021

AN:

151818

Hom.:

Cov.:

AF XY:

0.00690

AC XY:

512

AN XY:

74248

show subpopulations

Gnomad4 AFR

AF:

0.00429

Gnomad4 AMR

AF:

0.00315

Gnomad4 ASJ

AF:

0.0185

Gnomad4 EAS

AF:

0.00484

Gnomad4 SAS

AF:

0.0311

Gnomad4 FIN

AF:

0.00364

Gnomad4 NFE

AF:

0.00735

Gnomad4 OTH

AF:

0.00856

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

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 20, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2024	See Variant Classification Assertion Criteria. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 29, 2014

- -

AGRN-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 05, 2019

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 20, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.41

CADD

Benign

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

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-0.25

REVEL

Benign

0.040

Sift

Benign

0.63

Sift4G

Benign

0.19

Vest4

0.053

MPC

0.42

ClinPred

0.0045

GERP RS

1.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.19

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