1-1051820-C-T

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.5651+5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.892 in 1,613,352 control chromosomes in the GnomAD database, including 650,064 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.79 ( 50443 hom., cov: 34)

Exomes 𝑓: 0.90 ( 599621 hom. )

Consequence

AGRN
NM_198576.4 splice_region, intron

Scores

Splicing: ADA: 0.0002423

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.17

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 (BayesDel_noAF=-0.87).

BP6

Variant 1-1051820-C-T is Benign according to our data. Variant chr1-1051820-C-T is described in ClinVar as [Benign]. Clinvar id is 128317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1051820-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.972 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4 link	c.5651+5C>T		splice_region_variant, intron_variant	Intron 33 of 35	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.5651+5C>T		splice_region_variant, intron_variant	Intron 33 of 35	1	NM_198576.4	ENSP00000368678.2		O00468-6

Frequencies

GnomAD3 genomes

AF:

0.787

AC:

119733

AN:

152082

Hom.:

50443

Cov.:

show subpopulations

Gnomad AFR

AF:

0.453

Gnomad AMI

AF:

0.986

Gnomad AMR

AF:

0.886

Gnomad ASJ

AF:

0.895

Gnomad EAS

AF:

0.995

Gnomad SAS

AF:

0.887

Gnomad FIN

AF:

0.955

Gnomad MID

AF:

0.864

Gnomad NFE

AF:

0.911

Gnomad OTH

AF:

0.813

GnomAD3 exomes

AF:

0.887

AC:

221888

AN:

250118

Hom.:

100369

AF XY:

0.893

AC XY:

121065

AN XY:

135608

show subpopulations

Gnomad AFR exome

AF:

0.439

Gnomad AMR exome

AF:

0.932

Gnomad ASJ exome

AF:

0.892

Gnomad EAS exome

AF:

0.996

Gnomad SAS exome

AF:

0.883

Gnomad FIN exome

AF:

0.950

Gnomad NFE exome

AF:

0.908

Gnomad OTH exome

AF:

0.893

GnomAD4 exome

AF:

0.902

AC:

1318631

AN:

1461152

Hom.:

599621

Cov.:

AF XY:

0.903

AC XY:

656161

AN XY:

726882

show subpopulations

Gnomad4 AFR exome

AF:

0.424

Gnomad4 AMR exome

AF:

0.926

Gnomad4 ASJ exome

AF:

0.889

Gnomad4 EAS exome

AF:

0.998

Gnomad4 SAS exome

AF:

0.883

Gnomad4 FIN exome

AF:

0.947

Gnomad4 NFE exome

AF:

0.914

Gnomad4 OTH exome

AF:

0.882

GnomAD4 genome

AF:

0.787

AC:

119758

AN:

152200

Hom.:

50443

Cov.:

AF XY:

0.793

AC XY:

59011

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.452

Gnomad4 AMR

AF:

0.886

Gnomad4 ASJ

AF:

0.895

Gnomad4 EAS

AF:

0.995

Gnomad4 SAS

AF:

0.886

Gnomad4 FIN

AF:

0.955

Gnomad4 NFE

AF:

0.911

Gnomad4 OTH

AF:

0.816

Alfa

AF:

0.857

Hom.:

32550

Bravo

AF:

0.767

Asia WGS

AF:

0.913

AC:

3175

AN:

3478

EpiCase

AF:

0.904

EpiControl

AF:

0.898

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Jan 19, 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. -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital myasthenic syndrome 8

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.56

DANN

Benign

0.74

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00024

dbscSNV1_RF

Benign

0.016

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