1-1051352-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The ENST00000379370.7(AGRN):c.5353G>C(p.Asp1785His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000044 in 1,566,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1785N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

AGRN
ENST00000379370.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0220

Publications

8 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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09365985).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000379370.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AGRN	NM_198576.4	MANE Select	c.5353G>C	p.Asp1785His	missense	Exon 31 of 36	NP_940978.2
AGRN	NM_001305275.2		c.5365G>C	p.Asp1789His	missense	Exon 32 of 39	NP_001292204.1
AGRN	NM_001364727.2		c.5050G>C	p.Asp1684His	missense	Exon 31 of 36	NP_001351656.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AGRN	ENST00000379370.7	TSL:1 MANE Select	c.5353G>C	p.Asp1785His	missense	Exon 31 of 36	ENSP00000368678.2
AGRN	ENST00000651234.1		c.5050G>C	p.Asp1684His	missense	Exon 31 of 38	ENSP00000499046.1
AGRN	ENST00000652369.2		c.5038G>C	p.Asp1680His	missense	Exon 30 of 35	ENSP00000498543.1

Frequencies

GnomAD3 genomes

AF:

0.0000724

AC:

AN:

151944

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000105

AC:

AN:

172002

AF XY:

0.0000974

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000151

Gnomad ASJ exome

AF:

0.000235

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000410

AC:

AN:

1414356

Hom.:

Cov.:

AF XY:

0.0000386

AC XY:

AN XY:

699160

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32810

American (AMR)

AF:

0.000106

AC:

AN:

37580

Ashkenazi Jewish (ASJ)

AF:

0.000277

AC:

AN:

25268

East Asian (EAS)

AF:

0.00

AC:

AN:

37760

South Asian (SAS)

AF:

0.000385

AC:

AN:

80550

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47546

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5392

European-Non Finnish (NFE)

AF:

0.0000138

AC:

AN:

1088812

Other (OTH)

AF:

0.0000171

AC:

AN:

58638

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

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:

0.0000723

AC:

AN:

152062

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41512

American (AMR)

AF:

0.000196

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00124

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10562

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67924

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.539

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:

0.0000416

ExAC

AF:

0.0000944

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital myasthenic syndrome 8 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.82

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.62

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.094

MetaSVM

Benign

-1.0

PhyloP100

0.022

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.5

REVEL

Benign

0.23

Sift

Benign

0.18

Sift4G

Uncertain

0.035

Vest4

0.39

MVP

0.38

MPC

0.41

ClinPred

0.052

GERP RS

-2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

gMVP

0.46

Mutation Taster

=87/13

polymorphism

(source)

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

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over