Variant rs763818876 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_198576.4(AGRN):c.5611G>A(p.Gly1871Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,518 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

AGRN
NM_198576.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1O:1

Conservation

PhyloP100: 4.73

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.986

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4 linkuse as main transcript	c.5611G>A	p.Gly1871Arg	missense_variant	33/36	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.5611G>A	p.Gly1871Arg	missense_variant	33/36	1	NM_198576.4	ENSP00000368678	P1	O00468-6
AGRN	ENST00000651234.1 linkuse as main transcript	c.5308G>A	p.Gly1770Arg	missense_variant	33/38			ENSP00000499046
AGRN	ENST00000652369.1 linkuse as main transcript	c.5296G>A	p.Gly1766Arg	missense_variant	32/35			ENSP00000498543
AGRN	ENST00000620552.4 linkuse as main transcript	c.5209G>A	p.Gly1737Arg	missense_variant	34/39	5		ENSP00000484607

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000798

AC:

AN:

250674

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135812

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461518

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727076

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Congenital myasthenic syndrome 8

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1871 of the AGRN protein (p.Gly1871Arg). This variant is present in population databases (rs763818876, gnomAD 0.003%). This missense change has been observed in individual(s) with congenital myasthenic syndrome (PMID: 24951643). ClinVar contains an entry for this variant (Variation ID: 243040). 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 disruptive. 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. -

Congenital myasthenic syndrome

Other:1

not provided, no classification provided

literature only

GeneReviews

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.22

CADD

Uncertain

DANN

Uncertain

1.0

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.63

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Uncertain

-0.0093

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-6.2

D;.

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0030

D;.

Sift4G

Uncertain

0.0030

D;D

Vest4

0.90

MVP

0.82

MPC

0.63

ClinPred

0.95

GERP RS

4.8

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.8

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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