1-1020217-G-T

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.45G>T(p.Pro15Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.331 in 1,393,132 control chromosomes in the GnomAD database, including 77,454 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.31 ( 7500 hom., cov: 32)

Exomes 𝑓: 0.33 ( 69954 hom. )

Consequence

AGRN
NM_198576.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.853

Publications

12 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=-0.57).

BP6

Variant 1-1020217-G-T is Benign according to our data. Variant chr1-1020217-G-T is described in ClinVar as Benign. ClinVar VariationId is 128310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.853 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.337 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	NM_198576.4	MANE Select	c.45G>T	p.Pro15Pro	synonymous	Exon 1 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.45G>T	p.Pro15Pro	synonymous	Exon 1 of 39	NP_001292204.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	ENST00000379370.7	TSL:1 MANE Select	c.45G>T	p.Pro15Pro	synonymous	Exon 1 of 36	ENSP00000368678.2
	AGRN	ENST00000620552.4	TSL:5	c.-370G>T		5_prime_UTR	Exon 1 of 39	ENSP00000484607.1

Frequencies

GnomAD3 genomes

AF:

0.307

AC:

46469

AN:

151260

Hom.:

7503

Cov.:

show subpopulations

Gnomad AFR

AF:

0.263

Gnomad AMI

AF:

0.392

Gnomad AMR

AF:

0.234

Gnomad ASJ

AF:

0.282

Gnomad EAS

AF:

0.177

Gnomad SAS

AF:

0.319

Gnomad FIN

AF:

0.435

Gnomad MID

AF:

0.296

Gnomad NFE

AF:

0.341

Gnomad OTH

AF:

0.296

GnomAD2 exomes

AF:

0.343

AC:

17342

AN:

50582

AF XY:

0.344

show subpopulations

Gnomad AFR exome

AF:

0.317

Gnomad AMR exome

AF:

0.257

Gnomad ASJ exome

AF:

0.332

Gnomad EAS exome

AF:

0.235

Gnomad FIN exome

AF:

0.448

Gnomad NFE exome

AF:

0.366

Gnomad OTH exome

AF:

0.354

GnomAD4 exome

AF:

0.333

AC:

413987

AN:

1241764

Hom.:

69954

Cov.:

AF XY:

0.334

AC XY:

203698

AN XY:

610058

show subpopulations

African (AFR)

AF:

0.264

AC:

6553

AN:

24854

American (AMR)

AF:

0.246

AC:

4190

AN:

16998

Ashkenazi Jewish (ASJ)

AF:

0.296

AC:

5918

AN:

19982

East Asian (EAS)

AF:

0.172

AC:

4586

AN:

26658

South Asian (SAS)

AF:

0.327

AC:

19594

AN:

59960

European-Finnish (FIN)

AF:

0.420

AC:

13305

AN:

31716

Middle Eastern (MID)

AF:

0.239

AC:

851

AN:

3568

European-Non Finnish (NFE)

AF:

0.341

AC:

343058

AN:

1007512

Other (OTH)

AF:

0.315

AC:

15932

AN:

50516

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

13794

27589

41383

55178

68972

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11558

23116

34674

46232

57790

<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:

0.307

AC:

46464

AN:

151368

Hom.:

7500

Cov.:

AF XY:

0.309

AC XY:

22903

AN XY:

74004

show subpopulations

African (AFR)

AF:

0.262

AC:

10849

AN:

41374

American (AMR)

AF:

0.233

AC:

3551

AN:

15220

Ashkenazi Jewish (ASJ)

AF:

0.282

AC:

977

AN:

3464

East Asian (EAS)

AF:

0.177

AC:

913

AN:

5146

South Asian (SAS)

AF:

0.319

AC:

1540

AN:

4830

European-Finnish (FIN)

AF:

0.435

AC:

4504

AN:

10364

Middle Eastern (MID)

AF:

0.288

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.341

AC:

23071

AN:

67668

Other (OTH)

AF:

0.295

AC:

620

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1675

3349

5024

6698

8373

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

470

940

1410

1880

2350

<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:

0.319

Hom.:

971

Bravo

AF:

0.289

Asia WGS

AF:

0.241

AC:

819

AN:

3400

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Aug 29, 2014

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 04, 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.

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Congenital myasthenic syndrome 8

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.74

PhyloP100

0.85

PromoterAI

0.0031

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.4

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

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over