1-1049467-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_198576.4(AGRN):c.4514+16G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.017 in 1,600,510 control chromosomes in the GnomAD database, including 1,445 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.059 ( 732 hom., cov: 32)

Exomes 𝑓: 0.013 ( 713 hom. )

Consequence

AGRN
NM_198576.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.863

Publications

3 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 (BayesDel_noAF=-0.84).

BP6

Variant 1-1049467-G-C is Benign according to our data. Variant chr1-1049467-G-C is described in ClinVar as [Benign]. Clinvar id is 263186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4 link	c.4514+16G>C		intron_variant	Intron 25 of 35	ENST00000379370.7	NP_940978.2	O00468-6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7 link	c.4514+16G>C		intron_variant	Intron 25 of 35	1	NM_198576.4	ENSP00000368678.2		O00468-6

Frequencies

GnomAD3 genomes

AF:

0.0592

AC:

8999

AN:

152058

Hom.:

728

Cov.:

show subpopulations

Gnomad AFR

AF:

0.188

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.0281

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00642

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.00921

Gnomad OTH

AF:

0.0507

GnomAD2 exomes

AF:

0.0203

AC:

4813

AN:

236558

AF XY:

0.0162

show subpopulations

Gnomad AFR exome

AF:

0.194

Gnomad AMR exome

AF:

0.0154

Gnomad ASJ exome

AF:

0.00494

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00126

Gnomad NFE exome

AF:

0.00944

Gnomad OTH exome

AF:

0.0150

GnomAD4 exome

AF:

0.0125

AC:

18123

AN:

1448334

Hom.:

713

Cov.:

AF XY:

0.0118

AC XY:

8532

AN XY:

721038

show subpopulations

African (AFR)

AF:

0.195

AC:

6533

AN:

33454

American (AMR)

AF:

0.0171

AC:

762

AN:

44648

Ashkenazi Jewish (ASJ)

AF:

0.00529

AC:

138

AN:

26102

East Asian (EAS)

AF:

0.00

AC:

AN:

39670

South Asian (SAS)

AF:

0.00410

AC:

353

AN:

86130

European-Finnish (FIN)

AF:

0.00142

AC:

AN:

40800

Middle Eastern (MID)

AF:

0.0343

AC:

198

AN:

5766

European-Non Finnish (NFE)

AF:

0.00797

AC:

8858

AN:

1111530

Other (OTH)

AF:

0.0203

AC:

1223

AN:

60234

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

1073

2146

3218

4291

5364

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0594

AC:

9041

AN:

152176

Hom.:

732

Cov.:

AF XY:

0.0570

AC XY:

4242

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.188

AC:

7811

AN:

41486

American (AMR)

AF:

0.0280

AC:

428

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5156

South Asian (SAS)

AF:

0.00663

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000659

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00921

AC:

626

AN:

67990

Other (OTH)

AF:

0.0502

AC:

106

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

403

806

1209

1612

2015

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00242

Hom.:

Bravo

AF:

0.0683

Asia WGS

AF:

0.0160

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 20, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Congenital myasthenic syndrome 8

Benign:1

Feb 03, 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_noAF

Benign

-0.84

CADD

Benign

7.3

(source)

DANN

Benign

0.29

PhyloP100

0.86

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(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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1-1049467-G-C

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