rs777910926

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_198576.4(AGRN):c.4786C>T(p.Pro1596Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000143 in 1,612,188 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

AGRN
NM_198576.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.79

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

congenital myasthenic syndrome 8
Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
presynaptic congenital myasthenic syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
postsynaptic congenital myasthenic syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

AGRN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4 link	c.4786C>T	p.Pro1596Ser	missense_variant	Exon 27 of 36	ENST00000379370.7	NP_940978.2	O00468-6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AGRN	ENST00000379370.7 link	c.4786C>T	p.Pro1596Ser	missense_variant	Exon 27 of 36	1	NM_198576.4	ENSP00000368678.2	O00468-6
AGRN	ENST00000651234.1 link	c.4471C>T	p.Pro1491Ser	missense_variant	Exon 26 of 38			ENSP00000499046.1	A0A494C1I6
AGRN	ENST00000652369.2 link	c.4471C>T	p.Pro1491Ser	missense_variant	Exon 26 of 35			ENSP00000498543.1	A0A494C0G5
AGRN	ENST00000620552.4 link	c.4372C>T	p.Pro1458Ser	missense_variant	Exon 27 of 39	5		ENSP00000484607.1	A0A087X208

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000124

AC:

AN:

241050

AF XY:

0.0000227

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000283

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000890

AC:

AN:

1460014

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

726314

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33464

American (AMR)

AF:

0.00

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26090

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51874

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000117

AC:

AN:

1111808

Other (OTH)

AF:

0.00

AC:

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41448

American (AMR)

AF:

0.000523

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68000

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000110

ExAC

AF:

0.0000167

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Congenital myasthenic syndrome 8

Uncertain:1

Jan 29, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. This variant is present in population databases (rs777910926, ExAC 0.003%). This sequence change replaces proline with serine at codon 1596 of the AGRN protein (p.Pro1596Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant has not been reported in the literature in individuals with AGRN-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.016

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.97

D;D

M_CAP

Pathogenic

0.62

MetaRNN

Uncertain

0.73

D;D

MetaSVM

Uncertain

0.71

MutationAssessor

Uncertain

2.9

M;.

PhyloP100

3.8

PrimateAI

Benign

0.41

PROVEAN

Pathogenic

-4.8

D;.

REVEL

Uncertain

0.48

Sift

Uncertain

0.0040

D;.

Sift4G

Uncertain

0.0070

D;D

Vest4

0.55

MutPred

0.45

Loss of catalytic residue at P1596 (P = 0.0243);.;

MVP

0.89

MPC

0.48

ClinPred

0.94

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.64

Mutation Taster

=80/20

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over