rs3128098

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.2537-26A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.918 in 1,613,008 control chromosomes in the GnomAD database, including 683,964 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.85 ( 56745 hom., cov: 34)

Exomes 𝑓: 0.93 ( 627219 hom. )

Consequence

AGRN
NM_198576.4 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.863

Publications

8 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

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 1-1045707-A-G is Benign according to our data. Variant chr1-1045707-A-G is described in ClinVar as Benign. ClinVar VariationId is 263172.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

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	Effect	Exon Rank	Protein
AGRN	NM_198576.4	MANE Select	c.2537-26A>G	intron	N/A	NP_940978.2
AGRN	NM_001305275.2		c.2537-26A>G	intron	N/A	NP_001292204.1
AGRN	NM_001364727.2		c.2222-26A>G	intron	N/A	NP_001351656.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
AGRN	ENST00000379370.7	TSL:1 MANE Select	c.2537-26A>G	intron	N/A	ENSP00000368678.2
AGRN	ENST00000651234.1		c.2222-26A>G	intron	N/A	ENSP00000499046.1
AGRN	ENST00000652369.2		c.2222-26A>G	intron	N/A	ENSP00000498543.1

Frequencies

GnomAD3 genomes

AF:

0.854

AC:

129873

AN:

152106

Hom.:

56727

Cov.:

show subpopulations

Gnomad AFR

AF:

0.644

Gnomad AMI

AF:

0.992

Gnomad AMR

AF:

0.910

Gnomad ASJ

AF:

0.916

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.962

Gnomad FIN

AF:

0.960

Gnomad MID

AF:

0.896

Gnomad NFE

AF:

0.928

Gnomad OTH

AF:

0.868

GnomAD2 exomes

AF:

0.921

AC:

229847

AN:

249684

AF XY:

0.926

show subpopulations

Gnomad AFR exome

AF:

0.637

Gnomad AMR exome

AF:

0.946

Gnomad ASJ exome

AF:

0.919

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

0.956

Gnomad NFE exome

AF:

0.925

Gnomad OTH exome

AF:

0.916

GnomAD4 exome

AF:

0.925

AC:

1351529

AN:

1460784

Hom.:

627219

Cov.:

AF XY:

0.927

AC XY:

673516

AN XY:

726710

show subpopulations

African (AFR)

AF:

0.624

AC:

20894

AN:

33474

American (AMR)

AF:

0.941

AC:

42091

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.917

AC:

23947

AN:

26126

East Asian (EAS)

AF:

1.00

AC:

39686

AN:

39694

South Asian (SAS)

AF:

0.956

AC:

82436

AN:

86258

European-Finnish (FIN)

AF:

0.953

AC:

50021

AN:

52474

Middle Eastern (MID)

AF:

0.887

AC:

5115

AN:

5768

European-Non Finnish (NFE)

AF:

0.928

AC:

1032186

AN:

1111898

Other (OTH)

AF:

0.914

AC:

55153

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

6542

13084

19626

26168

32710

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21522

43044

64566

86088

107610

<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:

0.854

AC:

129943

AN:

152224

Hom.:

56745

Cov.:

AF XY:

0.858

AC XY:

63865

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.644

AC:

26719

AN:

41500

American (AMR)

AF:

0.911

AC:

13929

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.916

AC:

3182

AN:

3472

East Asian (EAS)

AF:

1.00

AC:

5173

AN:

5174

South Asian (SAS)

AF:

0.961

AC:

4645

AN:

4832

European-Finnish (FIN)

AF:

0.960

AC:

10195

AN:

10624

Middle Eastern (MID)

AF:

0.895

AC:

263

AN:

294

European-Non Finnish (NFE)

AF:

0.928

AC:

63095

AN:

68006

Other (OTH)

AF:

0.870

AC:

1837

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

870

1740

2609

3479

4349

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

882

1764

2646

3528

4410

<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:

0.896

Hom.:

11337

Bravo

AF:

0.839

Asia WGS

AF:

0.959

AC:

3335

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Congenital myasthenic syndrome 8 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

5.6

(source)

DANN

Benign

0.38

PhyloP100

-0.86

La Branchor

0.77

BranchPoint Hunter

1.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over