1-1053827-G-C

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.5726G>C(p.Ser1909Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00364 in 1,611,076 control chromosomes in the GnomAD database, including 193 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1909R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0072 ( 36 hom., cov: 33)

Exomes 𝑓: 0.0033 ( 157 hom. )

Consequence

AGRN
NM_198576.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.71

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=0.0057588816).

BP6

Variant 1-1053827-G-C is Benign according to our data. Variant chr1-1053827-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 128318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0564 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4 link	c.5726G>C	p.Ser1909Thr	missense_variant	Exon 34 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.5726G>C	p.Ser1909Thr	missense_variant	Exon 34 of 36	1	NM_198576.4	ENSP00000368678.2		O00468-6

Frequencies

GnomAD3 genomes

AF:

0.00711

AC:

1082

AN:

152280

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00215

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0590

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00961

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000411

Gnomad OTH

AF:

0.00573

GnomAD3 exomes

AF:

0.0125

AC:

3043

AN:

243286

Hom.:

106

AF XY:

0.00929

AC XY:

1228

AN XY:

132242

show subpopulations

Gnomad AFR exome

AF:

0.00156

Gnomad AMR exome

AF:

0.0821

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00702

Gnomad SAS exome

AF:

0.000302

Gnomad FIN exome

AF:

0.0000489

Gnomad NFE exome

AF:

0.000464

Gnomad OTH exome

AF:

0.00894

GnomAD4 exome

AF:

0.00327

AC:

4764

AN:

1458678

Hom.:

157

Cov.:

AF XY:

0.00283

AC XY:

2054

AN XY:

725460

show subpopulations

Gnomad4 AFR exome

AF:

0.000926

Gnomad4 AMR exome

AF:

0.0784

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0204

Gnomad4 SAS exome

AF:

0.000198

Gnomad4 FIN exome

AF:

0.0000191

Gnomad4 NFE exome

AF:

0.000220

Gnomad4 OTH exome

AF:

0.00307

GnomAD4 genome

AF:

0.00717

AC:

1093

AN:

152398

Hom.:

Cov.:

AF XY:

0.00782

AC XY:

583

AN XY:

74516

show subpopulations

Gnomad4 AFR

AF:

0.00214

Gnomad4 AMR

AF:

0.0596

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00982

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000412

Gnomad4 OTH

AF:

0.00567

Alfa

AF:

0.00248

Hom.:

Bravo

AF:

0.0112

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.000582

AC:

ExAC

AF:

0.00910

AC:

1102

Asia WGS

AF:

0.00520

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital myasthenic syndrome 8

Benign:1

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: 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

-0.41

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Benign

0.50

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.87

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

D;D

MetaRNN

Benign

0.0058

T;T

MetaSVM

Benign

-0.89

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.4

N;.

REVEL

Uncertain

0.32

Sift

Benign

0.58

T;.

Sift4G

Uncertain

0.036

D;D

Vest4

0.53

MPC

0.39

ClinPred

0.035

GERP RS

-0.78

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.55

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