rs138288952

Positions:

chr1-1043382-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_198576.4(AGRN):c.1528G>A(p.Gly510Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0103 in 1,609,070 control chromosomes in the GnomAD database, including 105 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0081 ( 10 hom., cov: 33)

Exomes 𝑓: 0.011 ( 95 hom. )

Consequence

AGRN
NM_198576.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.61

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=0.012149155).

BP6

Variant 1-1043382-G-A is Benign according to our data. Variant chr1-1043382-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 263163.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1043382-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00811 (1236/152322) while in subpopulation NFE AF= 0.0134 (908/68014). AF 95% confidence interval is 0.0126. There are 10 homozygotes in gnomad4. There are 599 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4 linkuse as main transcript	c.1528G>A	p.Gly510Ser	missense_variant	8/36	ENST00000379370.7	NP_940978.2	O00468-6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
AGRN	ENST00000379370.7 linkuse as main transcript	c.1528G>A	p.Gly510Ser	missense_variant	8/36	1	NM_198576.4	ENSP00000368678.2	O00468-6
AGRN	ENST00000651234.1 linkuse as main transcript	c.1213G>A	p.Gly405Ser	missense_variant	7/38			ENSP00000499046.1	A0A494C1I6
AGRN	ENST00000652369.1 linkuse as main transcript	c.1213G>A	p.Gly405Ser	missense_variant	7/35			ENSP00000498543.1	A0A494C0G5
AGRN	ENST00000620552.4 linkuse as main transcript	c.1114G>A	p.Gly372Ser	missense_variant	8/39	5		ENSP00000484607.1	A0A087X208

Frequencies

GnomAD3 genomes

AF:

0.00812

AC:

1236

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00212

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00713

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00715

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0133

Gnomad OTH

AF:

0.00812

GnomAD3 exomes

AF:

0.00767

AC:

1824

AN:

237686

Hom.:

AF XY:

0.00758

AC XY:

980

AN XY:

129224

show subpopulations

Gnomad AFR exome

AF:

0.00173

Gnomad AMR exome

AF:

0.00557

Gnomad ASJ exome

AF:

0.00873

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00178

Gnomad FIN exome

AF:

0.00831

Gnomad NFE exome

AF:

0.0117

Gnomad OTH exome

AF:

0.0102

GnomAD4 exome

AF:

0.0105

AC:

15353

AN:

1456748

Hom.:

Cov.:

AF XY:

0.0103

AC XY:

7468

AN XY:

724508

show subpopulations

Gnomad4 AFR exome

AF:

0.00152

Gnomad4 AMR exome

AF:

0.00544

Gnomad4 ASJ exome

AF:

0.00920

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00177

Gnomad4 FIN exome

AF:

0.00852

Gnomad4 NFE exome

AF:

0.0124

Gnomad4 OTH exome

AF:

0.00794

GnomAD4 genome

AF:

0.00811

AC:

1236

AN:

152322

Hom.:

Cov.:

AF XY:

0.00804

AC XY:

599

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00212

Gnomad4 AMR

AF:

0.00712

Gnomad4 ASJ

AF:

0.00749

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.00715

Gnomad4 NFE

AF:

0.0134

Gnomad4 OTH

AF:

0.00803

Alfa

AF:

0.0119

Hom.:

Bravo

AF:

0.00742

TwinsUK

AF:

0.00728

AC:

ALSPAC

AF:

0.0109

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.0126

AC:

108

ExAC

AF:

0.00703

AC:

849

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 15, 2016	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	AGRN: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Congenital myasthenic syndrome 8

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Uncertain

1.0

Eigen

Uncertain

0.19

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.76

T;T

MetaRNN

Benign

0.012

T;T

MetaSVM

Benign

-0.77

MutationAssessor

Benign

0.33

N;.

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-2.7

D;.

REVEL

Benign

0.20

Sift

Benign

0.24

T;.

Sift4G

Benign

0.28

T;T

Vest4

0.36

MVP

0.70

MPC

0.55

ClinPred

0.025

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

gMVP

0.46

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