NM_198576.4:c.3866C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_198576.4(AGRN):c.3866C>T(p.Pro1289Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00599 in 1,570,118 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict 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. P1289S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0063 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0060 ( 29 hom. )

Consequence

AGRN
NM_198576.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -2.61

Publications

6 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003664583).

BP6

Variant 1-1048126-C-T is Benign according to our data. Variant chr1-1048126-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 128304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00629 (958/152314) while in subpopulation AFR AF = 0.009 (374/41558). AF 95% confidence interval is 0.00825. There are 5 homozygotes in GnomAd4. There are 452 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4 link	c.3866C>T	p.Pro1289Leu	missense_variant	Exon 23 of 36	ENST00000379370.7	NP_940978.2	O00468-6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AGRN	ENST00000379370.7 link	c.3866C>T	p.Pro1289Leu	missense_variant	Exon 23 of 36	1	NM_198576.4	ENSP00000368678.2	O00468-6
AGRN	ENST00000651234.1 link	c.3551C>T	p.Pro1184Leu	missense_variant	Exon 22 of 38			ENSP00000499046.1	A0A494C1I6
AGRN	ENST00000652369.2 link	c.3551C>T	p.Pro1184Leu	missense_variant	Exon 22 of 35			ENSP00000498543.1	A0A494C0G5
AGRN	ENST00000620552.4 link	c.3452C>T	p.Pro1151Leu	missense_variant	Exon 23 of 39	5		ENSP00000484607.1	A0A087X208

Frequencies

GnomAD3 genomes

AF:

0.00628

AC:

956

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00898

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.00386

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.000847

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00695

Gnomad OTH

AF:

0.00669

GnomAD2 exomes

AF:

0.00496

AC:

899

AN:

181330

AF XY:

0.00488

show subpopulations

Gnomad AFR exome

AF:

0.00953

Gnomad AMR exome

AF:

0.00284

Gnomad ASJ exome

AF:

0.000564

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00141

Gnomad NFE exome

AF:

0.00779

Gnomad OTH exome

AF:

0.00472

GnomAD4 exome

AF:

0.00596

AC:

8454

AN:

1417804

Hom.:

Cov.:

AF XY:

0.00587

AC XY:

4129

AN XY:

703066

show subpopulations

African (AFR)

AF:

0.00937

AC:

305

AN:

32534

American (AMR)

AF:

0.00308

AC:

127

AN:

41272

Ashkenazi Jewish (ASJ)

AF:

0.000821

AC:

AN:

25592

East Asian (EAS)

AF:

0.0000269

AC:

AN:

37182

South Asian (SAS)

AF:

0.00305

AC:

249

AN:

81696

European-Finnish (FIN)

AF:

0.00134

AC:

AN:

37226

Middle Eastern (MID)

AF:

0.00560

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.00672

AC:

7375

AN:

1097534

Other (OTH)

AF:

0.00498

AC:

294

AN:

59050

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

552

1104

1655

2207

2759

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00629

AC:

958

AN:

152314

Hom.:

Cov.:

AF XY:

0.00607

AC XY:

452

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.00900

AC:

374

AN:

41558

American (AMR)

AF:

0.00385

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00414

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000847

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00695

AC:

473

AN:

68018

Other (OTH)

AF:

0.00662

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

100

149

199

249

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00641

Hom.:

Bravo

AF:

0.00696

ESP6500AA

AF:

0.00652

AC:

ESP6500EA

AF:

0.00682

AC:

ExAC

AF:

0.00439

AC:

518

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:7

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 25, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

AGRN: BP4, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 04, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Congenital myasthenic syndrome 8

Benign:1

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.35

(source)

DANN

Benign

0.66

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.0085

LIST_S2

Benign

0.26

T;T

MetaRNN

Benign

0.0037

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.81

N;.

PhyloP100

-2.6

PrimateAI

Benign

0.40

PROVEAN

Benign

0.29

N;.

REVEL

Benign

0.059

Sift

Benign

0.40

T;.

Sift4G

Benign

1.0

T;T

Vest4

0.092

MVP

0.54

MPC

0.12

ClinPred

0.0028

GERP RS

-4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.14

Mutation Taster

=100/0

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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NM_198576.4:c.3866C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over