1-1045444-G-C

Position:

chr1-1045444-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_198576.4(AGRN):c.2457G>C(p.Gly819Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00703 in 1,612,524 control chromosomes in the GnomAD database, including 176 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G819G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.021 ( 68 hom., cov: 33)

Exomes 𝑓: 0.0056 ( 108 hom. )

Consequence

AGRN
NM_198576.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.188

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:

AGRN (HGNC:):

AGRN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.67).

BP6

Variant 1-1045444-G-C is Benign according to our data. Variant chr1-1045444-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 190974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1045444-G-C is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.188 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0545 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4 linkuse as main transcript	c.2457G>C	p.Gly819Gly	synonymous_variant	14/36	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.2457G>C	p.Gly819Gly	synonymous_variant	14/36	1	NM_198576.4	ENSP00000368678.2		O00468-6

Frequencies

GnomAD3 genomes

AF:

0.0205

AC:

3113

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0563

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0106

Gnomad ASJ

AF:

0.00374

Gnomad EAS

AF:

0.0316

Gnomad SAS

AF:

0.00952

Gnomad FIN

AF:

0.0190

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00243

Gnomad OTH

AF:

0.0129

GnomAD3 exomes

AF:

0.0109

AC:

2707

AN:

249244

Hom.:

AF XY:

0.0102

AC XY:

1375

AN XY:

135284

show subpopulations

Gnomad AFR exome

AF:

0.0553

Gnomad AMR exome

AF:

0.00565

Gnomad ASJ exome

AF:

0.00571

Gnomad EAS exome

AF:

0.0269

Gnomad SAS exome

AF:

0.00840

Gnomad FIN exome

AF:

0.0198

Gnomad NFE exome

AF:

0.00300

Gnomad OTH exome

AF:

0.00886

GnomAD4 exome

AF:

0.00562

AC:

8210

AN:

1460184

Hom.:

108

Cov.:

AF XY:

0.00555

AC XY:

4031

AN XY:

726366

show subpopulations

Gnomad4 AFR exome

AF:

0.0579

Gnomad4 AMR exome

AF:

0.00595

Gnomad4 ASJ exome

AF:

0.00547

Gnomad4 EAS exome

AF:

0.0299

Gnomad4 SAS exome

AF:

0.00923

Gnomad4 FIN exome

AF:

0.0183

Gnomad4 NFE exome

AF:

0.00209

Gnomad4 OTH exome

AF:

0.00914

GnomAD4 genome

AF:

0.0205

AC:

3126

AN:

152340

Hom.:

Cov.:

AF XY:

0.0210

AC XY:

1566

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.0564

Gnomad4 AMR

AF:

0.0106

Gnomad4 ASJ

AF:

0.00374

Gnomad4 EAS

AF:

0.0315

Gnomad4 SAS

AF:

0.00973

Gnomad4 FIN

AF:

0.0190

Gnomad4 NFE

AF:

0.00243

Gnomad4 OTH

AF:

0.0128

Alfa

AF:

0.00299

Hom.:

Bravo

AF:

0.0206

EpiCase

AF:

0.00224

EpiControl

AF:

0.00261

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	Dec 31, 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. -
Likely benign, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Sep 28, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Congenital myasthenic syndrome 8

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

2.3

DANN

Benign

0.30

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

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