rs147259096

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_198576.4(AGRN):c.4840G>A(p.Glu1614Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0021 in 1,611,426 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0022 ( 6 hom. )

Consequence

AGRN
NM_198576.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 2.64

Publications

5 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: DEFINITIVE, STRONG Submitted by: ClinGen, 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.067908466).

BP6

Variant 1-1049998-G-A is Benign according to our data. Variant chr1-1049998-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 474139.

BS2

High Homozygotes in GnomAdExome4 at 6 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	UniProt
AGRN	NM_198576.4	MANE Select	c.4840G>A	p.Glu1614Lys	missense	Exon 27 of 36	NP_940978.2
AGRN	NM_001305275.2		c.4840G>A	p.Glu1614Lys	missense	Exon 27 of 39	NP_001292204.1	O00468-1
AGRN	NM_001364727.2		c.4525G>A	p.Glu1509Lys	missense	Exon 26 of 36	NP_001351656.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AGRN	ENST00000379370.7	TSL:1 MANE Select	c.4840G>A	p.Glu1614Lys	missense	Exon 27 of 36	ENSP00000368678.2	O00468-6
AGRN	ENST00000651234.1		c.4525G>A	p.Glu1509Lys	missense	Exon 26 of 38	ENSP00000499046.1	A0A494C1I6
AGRN	ENST00000652369.2		c.4525G>A	p.Glu1509Lys	missense	Exon 26 of 35	ENSP00000498543.1	A0A494C0G5

Frequencies

GnomAD3 genomes

AF:

0.00114

AC:

174

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000700

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

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:

0.00188

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.000915

AC:

217

AN:

237190

AF XY:

0.000872

show subpopulations

Gnomad AFR exome

AF:

0.000278

Gnomad AMR exome

AF:

0.000853

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00166

Gnomad OTH exome

AF:

0.00155

GnomAD4 exome

AF:

0.00220

AC:

3207

AN:

1459240

Hom.:

Cov.:

AF XY:

0.00214

AC XY:

1551

AN XY:

725926

show subpopulations

African (AFR)

AF:

0.000598

AC:

AN:

33470

American (AMR)

AF:

0.00112

AC:

AN:

44566

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26064

East Asian (EAS)

AF:

0.00

AC:

AN:

39656

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86118

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51706

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00273

AC:

3031

AN:

1111622

Other (OTH)

AF:

0.00169

AC:

102

AN:

60280

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

196

392

588

784

980

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

252

378

504

630

<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:

0.00114

AC:

174

AN:

152186

Hom.:

Cov.:

AF XY:

0.000887

AC XY:

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.000698

AC:

AN:

41536

American (AMR)

AF:

0.000784

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00188

AC:

128

AN:

67962

Other (OTH)

AF:

0.00237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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:

0.00228

Hom.:

Bravo

AF:

0.00116

ESP6500AA

AF:

0.000457

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.000696

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00136

EpiControl

AF:

0.00196

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Congenital myasthenic syndrome 8 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.96

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.94

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.91

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.068

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.44

PhyloP100

2.6

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.1

REVEL

Benign

0.26

Sift

Benign

0.52

Sift4G

Uncertain

0.060

Vest4

0.58

MVP

0.71

MPC

0.17

ClinPred

0.0072

GERP RS

1.9

gMVP

0.76

Mutation Taster

=82/18

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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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

Computational scores

Splicing

Publications

Other links and lift over