rs6657048

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_198576.4(AGRN):c.261C>T(p.Asp87Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0162 in 1,613,184 control chromosomes in the GnomAD database, including 425 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.029 ( 123 hom., cov: 34)

Exomes 𝑓: 0.015 ( 302 hom. )

Consequence

AGRN
NM_198576.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -2.21

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 1-1022260-C-T is Benign according to our data. Variant chr1-1022260-C-T is described in ClinVar as Benign. ClinVar VariationId is 128296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.21 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0665 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4 link	c.261C>T	p.Asp87Asp	synonymous_variant	Exon 2 of 36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
AGRN	ENST00000379370.7 link	c.261C>T	p.Asp87Asp	synonymous_variant	Exon 2 of 36	1	NM_198576.4	ENSP00000368678.2
AGRN	ENST00000620552.4 link	c.-154C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 39	5		ENSP00000484607.1
AGRN	ENST00000620552.4 link	c.-154C>T		5_prime_UTR_variant	Exon 2 of 39	5		ENSP00000484607.1

Frequencies

GnomAD3 genomes

AF:

0.0288

AC:

4384

AN:

152188

Hom.:

123

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0687

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.0108

Gnomad ASJ

AF:

0.0187

Gnomad EAS

AF:

0.00538

Gnomad SAS

AF:

0.0356

Gnomad FIN

AF:

0.00443

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0146

Gnomad OTH

AF:

0.0287

GnomAD2 exomes

AF:

0.0181

AC:

4549

AN:

250898

AF XY:

0.0187

show subpopulations

Gnomad AFR exome

AF:

0.0726

Gnomad AMR exome

AF:

0.00633

Gnomad ASJ exome

AF:

0.0168

Gnomad EAS exome

AF:

0.00413

Gnomad FIN exome

AF:

0.00508

Gnomad NFE exome

AF:

0.0143

Gnomad OTH exome

AF:

0.0135

GnomAD4 exome

AF:

0.0148

AC:

21676

AN:

1460878

Hom.:

302

Cov.:

AF XY:

0.0155

AC XY:

11265

AN XY:

726746

show subpopulations

African (AFR)

AF:

0.0725

AC:

2427

AN:

33480

American (AMR)

AF:

0.00729

AC:

326

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0187

AC:

489

AN:

26136

East Asian (EAS)

AF:

0.00189

AC:

AN:

39696

South Asian (SAS)

AF:

0.0363

AC:

3127

AN:

86258

European-Finnish (FIN)

AF:

0.00644

AC:

338

AN:

52468

Middle Eastern (MID)

AF:

0.0243

AC:

140

AN:

5768

European-Non Finnish (NFE)

AF:

0.0124

AC:

13743

AN:

1111970

Other (OTH)

AF:

0.0167

AC:

1011

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

1366

2733

4099

5466

6832

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

534

1068

1602

2136

2670

<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:

0.0288

AC:

4387

AN:

152306

Hom.:

123

Cov.:

AF XY:

0.0281

AC XY:

2092

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.0686

AC:

2849

AN:

41544

American (AMR)

AF:

0.0108

AC:

165

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0187

AC:

AN:

3470

East Asian (EAS)

AF:

0.00520

AC:

AN:

5188

South Asian (SAS)

AF:

0.0358

AC:

173

AN:

4830

European-Finnish (FIN)

AF:

0.00443

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0146

AC:

993

AN:

68028

Other (OTH)

AF:

0.0279

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

213

427

640

854

1067

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

150

200

250

<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:

0.0199

Hom.:

Bravo

AF:

0.0307

Asia WGS

AF:

0.0190

AC:

AN:

3478

EpiCase

AF:

0.0172

EpiControl

AF:

0.0154

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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. -

Sep 21, 2020

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 03, 2017

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

-0.62

CADD

Benign

0.59

(source)

DANN

Benign

0.87

PhyloP100

-2.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

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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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