Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_198576.4(AGRN):c.752T>C(p.Val251Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000161 in 1,462,122 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V251M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0012 ( 2 hom., cov: 31)

Exomes 𝑓: 0.000044 ( 1 hom. )

Consequence

AGRN
NM_198576.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 5.65

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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009522587).

BP6

Variant 1-1041197-T-C is Benign according to our data. Variant chr1-1041197-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 430121.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00118 (178/151120) while in subpopulation AFR AF = 0.00411 (169/41094). AF 95% confidence interval is 0.00361. There are 2 homozygotes in GnomAd4. There are 91 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR,AD gene

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.752T>C	p.Val251Ala	missense	Exon 5 of 36	NP_940978.2
AGRN	NM_001305275.2		c.752T>C	p.Val251Ala	missense	Exon 5 of 39	NP_001292204.1
AGRN	NM_001364727.2		c.437T>C	p.Val146Ala	missense	Exon 4 of 36	NP_001351656.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AGRN	ENST00000379370.7	TSL:1 MANE Select	c.752T>C	p.Val251Ala	missense	Exon 5 of 36	ENSP00000368678.2
AGRN	ENST00000651234.1		c.437T>C	p.Val146Ala	missense	Exon 4 of 38	ENSP00000499046.1
AGRN	ENST00000652369.2		c.437T>C	p.Val146Ala	missense	Exon 4 of 35	ENSP00000498543.1

Frequencies

GnomAD3 genomes

AF:

0.00118

AC:

178

AN:

151014

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00412

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

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:

0.0000295

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.000102

AC:

AN:

78762

AF XY:

0.000110

show subpopulations

Gnomad AFR exome

AF:

0.00559

Gnomad AMR exome

AF:

0.0000690

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000329

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000442

AC:

AN:

1311002

Hom.:

Cov.:

AF XY:

0.0000340

AC XY:

AN XY:

647120

show subpopulations

African (AFR)

AF:

0.00158

AC:

AN:

25872

American (AMR)

AF:

0.0000390

AC:

AN:

25624

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22412

East Asian (EAS)

AF:

0.00

AC:

AN:

27840

South Asian (SAS)

AF:

0.0000138

AC:

AN:

72590

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32762

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4800

European-Non Finnish (NFE)

AF:

0.00000478

AC:

AN:

1045280

Other (OTH)

AF:

0.000186

AC:

AN:

53822

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.00118

AC:

178

AN:

151120

Hom.:

Cov.:

AF XY:

0.00123

AC XY:

AN XY:

73878

show subpopulations

African (AFR)

AF:

0.00411

AC:

169

AN:

41094

American (AMR)

AF:

0.000197

AC:

AN:

15224

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

5134

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10384

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000295

AC:

AN:

67702

Other (OTH)

AF:

0.00190

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00199

Hom.:

ExAC

AF:

0.0000596

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

AGRN-related disorder (1)

Congenital myasthenic syndrome 8 (1)

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.96

MetaRNN

Benign

0.0095

MetaSVM

Benign

-0.33

MutationAssessor

Uncertain

2.5

PhyloP100

5.7

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-1.8

REVEL

Uncertain

0.35

Sift

Benign

0.10

Sift4G

Benign

0.12

Vest4

0.44

MutPred

0.24

Loss of stability (P = 0.0254)

MVP

0.84

MPC

0.64

ClinPred

0.058

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.65

Mutation Taster

=58/42

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.

rs779170859

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