NM_198576.4:c.3719C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_198576.4(AGRN):c.3719C>T(p.Pro1240Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00238 in 1,605,870 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1240Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0021 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0024 ( 9 hom. )

Consequence

AGRN
NM_198576.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 4.04

Publications

11 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 -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04960853).

BP6

Variant 1-1047863-C-T is Benign according to our data. Variant chr1-1047863-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 263182.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 9 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.3719C>T	p.Pro1240Leu	missense	Exon 22 of 36	NP_940978.2
AGRN	NM_001305275.2		c.3719C>T	p.Pro1240Leu	missense	Exon 22 of 39	NP_001292204.1
AGRN	NM_001364727.2		c.3404C>T	p.Pro1135Leu	missense	Exon 21 of 36	NP_001351656.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AGRN	ENST00000379370.7	TSL:1 MANE Select	c.3719C>T	p.Pro1240Leu	missense	Exon 22 of 36	ENSP00000368678.2
AGRN	ENST00000651234.1		c.3404C>T	p.Pro1135Leu	missense	Exon 21 of 38	ENSP00000499046.1
AGRN	ENST00000652369.2		c.3404C>T	p.Pro1135Leu	missense	Exon 21 of 35	ENSP00000498543.1

Frequencies

GnomAD3 genomes

AF:

0.00214

AC:

325

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00288

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00226

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00346

Gnomad OTH

AF:

0.000959

GnomAD2 exomes

AF:

0.00191

AC:

434

AN:

227228

AF XY:

0.00190

show subpopulations

Gnomad AFR exome

AF:

0.000225

Gnomad AMR exome

AF:

0.00112

Gnomad ASJ exome

AF:

0.00296

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00242

Gnomad NFE exome

AF:

0.00306

Gnomad OTH exome

AF:

0.00250

GnomAD4 exome

AF:

0.00240

AC:

3494

AN:

1453648

Hom.:

Cov.:

AF XY:

0.00235

AC XY:

1699

AN XY:

722568

show subpopulations

African (AFR)

AF:

0.000390

AC:

AN:

33346

American (AMR)

AF:

0.00130

AC:

AN:

43862

Ashkenazi Jewish (ASJ)

AF:

0.00316

AC:

AN:

25918

East Asian (EAS)

AF:

0.00

AC:

AN:

39360

South Asian (SAS)

AF:

0.0000235

AC:

AN:

85222

European-Finnish (FIN)

AF:

0.00311

AC:

159

AN:

51080

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.00275

AC:

3053

AN:

1109126

Other (OTH)

AF:

0.00213

AC:

128

AN:

59994

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

248

496

745

993

1241

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

216

324

432

540

<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:

0.00214

AC:

325

AN:

152222

Hom.:

Cov.:

AF XY:

0.00206

AC XY:

153

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41538

American (AMR)

AF:

0.00288

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00226

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00346

AC:

235

AN:

67996

Other (OTH)

AF:

0.000949

AC:

AN:

2108

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

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:

0.00288

Hom.:

Bravo

AF:

0.00167

ESP6500AA

AF:

0.000458

AC:

ESP6500EA

AF:

0.00293

AC:

ExAC

AF:

0.00205

AC:

246

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

AGRN-related disorder

Benign:1

Aug 25, 2021

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Congenital myasthenic syndrome 8

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

M_CAP

Pathogenic

0.36

MetaRNN

Benign

0.050

MetaSVM

Uncertain

-0.14

MutationAssessor

Uncertain

2.3

PhyloP100

4.0

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-5.2

REVEL

Uncertain

0.55

Sift

Benign

0.13

Sift4G

Pathogenic

0.0

Vest4

0.73

MVP

0.86

MPC

0.57

ClinPred

0.064

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.75

Mutation Taster

=83/17

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

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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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over