rs373657385

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_198576.4(AGRN):c.4517C>T(p.Ala1506Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000472 in 1,589,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. 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. A1506T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

AGRN
NM_198576.4 missense, splice_region

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.341

Publications

1 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 -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.035694003).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198576.4. 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.4517C>T	p.Ala1506Val	missense splice_region	Exon 26 of 36	NP_940978.2
AGRN	NM_001305275.2		c.4517C>T	p.Ala1506Val	missense splice_region	Exon 26 of 39	NP_001292204.1
AGRN	NM_001364727.2		c.4202C>T	p.Ala1401Val	missense splice_region	Exon 25 of 36	NP_001351656.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AGRN	ENST00000379370.7	TSL:1 MANE Select	c.4517C>T	p.Ala1506Val	missense splice_region	Exon 26 of 36	ENSP00000368678.2
AGRN	ENST00000651234.1		c.4202C>T	p.Ala1401Val	missense splice_region	Exon 25 of 38	ENSP00000499046.1
AGRN	ENST00000652369.2		c.4202C>T	p.Ala1401Val	missense splice_region	Exon 25 of 35	ENSP00000498543.1

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000785

AC:

AN:

203722

AF XY:

0.0000814

show subpopulations

Gnomad AFR exome

AF:

0.000503

Gnomad AMR exome

AF:

0.0000680

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000661

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000112

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000410

AC:

AN:

1437556

Hom.:

Cov.:

AF XY:

0.0000449

AC XY:

AN XY:

713018

show subpopulations

African (AFR)

AF:

0.000543

AC:

AN:

33136

American (AMR)

AF:

0.0000740

AC:

AN:

40556

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25610

East Asian (EAS)

AF:

0.000207

AC:

AN:

38630

South Asian (SAS)

AF:

0.000228

AC:

AN:

83442

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49690

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.00000908

AC:

AN:

1101282

Other (OTH)

AF:

0.0000168

AC:

AN:

59474

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

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:

0.000105

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.000314

AC:

AN:

41428

American (AMR)

AF:

0.000131

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

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:

0.000130

Hom.:

Bravo

AF:

0.000136

ESP6500AA

AF:

0.000689

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000751

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital myasthenic syndrome 8 (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.049

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.52

CADD

Benign

2.2

(source)

DANN

Benign

0.28

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.69

M_CAP

Benign

0.063

MetaRNN

Benign

0.036

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.93

PhyloP100

0.34

PrimateAI

Benign

0.42

PROVEAN

Benign

1.2

REVEL

Benign

0.091

Sift

Benign

1.0

Sift4G

Benign

1.0

Vest4

0.15

MVP

0.49

MPC

0.13

ClinPred

0.0036

GERP RS

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

gMVP

0.42

Mutation Taster

=90/10

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