chr1-1045996-C-T

Position:

chr1-1045996-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_198576.4(AGRN):c.2713C>T(p.Arg905Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000372 in 1,613,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00039 ( 0 hom. )

Consequence

AGRN
NM_198576.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.679

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16431165).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4 linkuse as main transcript	c.2713C>T	p.Arg905Cys	missense_variant	16/36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7 linkuse as main transcript	c.2713C>T	p.Arg905Cys	missense_variant	16/36	1	NM_198576.4	ENSP00000368678	P1	O00468-6

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000470

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000291

AC:

AN:

250498

Hom.:

AF XY:

0.000332

AC XY:

AN XY:

135698

show subpopulations

Gnomad AFR exome

AF:

0.0000618

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000490

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.000460

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000386

AC:

564

AN:

1461636

Hom.:

Cov.:

AF XY:

0.000392

AC XY:

285

AN XY:

727126

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000429

Gnomad4 FIN exome

AF:

0.0000376

Gnomad4 NFE exome

AF:

0.000456

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000237

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000470

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000406

Hom.:

Bravo

AF:

0.000253

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000354

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000533

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

The c.2713C>T (p.R905C) alteration is located in exon 16 (coding exon 16) of the AGRN gene. This alteration results from a C to T substitution at nucleotide position 2713, causing the arginine (R) at amino acid position 905 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Congenital myasthenic syndrome 8

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 905 of the AGRN protein (p.Arg905Cys). This variant is present in population databases (rs199593375, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with AGRN-related conditions. ClinVar contains an entry for this variant (Variation ID: 474108). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

1.0

Eigen

Benign

-0.0041

Eigen_PC

Benign

-0.099

FATHMM_MKL

Benign

0.50

LIST_S2

Pathogenic

0.97

D;D

M_CAP

Uncertain

0.096

MetaRNN

Benign

0.16

T;T

MetaSVM

Benign

-0.67

MutationAssessor

Uncertain

2.6

M;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.35

PROVEAN

Benign

-2.1

N;.

REVEL

Benign

0.22

Sift

Benign

0.055

T;.

Sift4G

Benign

0.074

T;T

Vest4

0.21

MVP

0.87

MPC

0.18

ClinPred

0.047

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.32

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