rs191270495

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_198576.4(AGRN):c.729C>G(p.Gly243Gly) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00224 in 1,399,664 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0092 ( 30 hom., cov: 31)

Exomes 𝑓: 0.0014 ( 31 hom. )

Consequence

AGRN
NM_198576.4 splice_region, synonymous

Scores

Splicing: ADA: 0.00002772

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.244

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 1-1041174-C-G is Benign according to our data. Variant chr1-1041174-C-G is described in ClinVar as Benign. ClinVar VariationId is 263202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.244 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00916 (1357/148196) while in subpopulation AFR AF = 0.0248 (970/39084). AF 95% confidence interval is 0.0235. There are 30 homozygotes in GnomAd4. There are 680 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 30 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4 link	c.729C>G	p.Gly243Gly	splice_region_variant, synonymous_variant	Exon 5 of 36	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.729C>G	p.Gly243Gly	splice_region_variant, synonymous_variant	Exon 5 of 36	1	NM_198576.4	ENSP00000368678.2		O00468-6

Frequencies

GnomAD3 genomes

AF:

0.00912

AC:

1350

AN:

148100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0247

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00696

Gnomad ASJ

AF:

0.00290

Gnomad EAS

AF:

0.0145

Gnomad SAS

AF:

0.00419

Gnomad FIN

AF:

0.00918

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00114

Gnomad OTH

AF:

0.00485

GnomAD2 exomes

AF:

0.00564

AC:

289

AN:

51286

AF XY:

0.00581

show subpopulations

Gnomad AFR exome

AF:

0.0326

Gnomad AMR exome

AF:

0.00340

Gnomad ASJ exome

AF:

0.00574

Gnomad EAS exome

AF:

0.0195

Gnomad FIN exome

AF:

0.0146

Gnomad NFE exome

AF:

0.00211

Gnomad OTH exome

AF:

0.00940

GnomAD4 exome

AF:

0.00142

AC:

1780

AN:

1251468

Hom.:

Cov.:

AF XY:

0.00139

AC XY:

855

AN XY:

615400

show subpopulations

African (AFR)

AF:

0.0135

AC:

307

AN:

22756

American (AMR)

AF:

0.00204

AC:

AN:

18136

Ashkenazi Jewish (ASJ)

AF:

0.00163

AC:

AN:

20192

East Asian (EAS)

AF:

0.0197

AC:

504

AN:

25596

South Asian (SAS)

AF:

0.000701

AC:

AN:

64196

European-Finnish (FIN)

AF:

0.0109

AC:

340

AN:

31114

Middle Eastern (MID)

AF:

0.00339

AC:

AN:

3834

European-Non Finnish (NFE)

AF:

0.000330

AC:

335

AN:

1014918

Other (OTH)

AF:

0.00327

AC:

166

AN:

50726

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

106

213

319

426

532

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00916

AC:

1357

AN:

148196

Hom.:

Cov.:

AF XY:

0.00940

AC XY:

680

AN XY:

72358

show subpopulations

African (AFR)

AF:

0.0248

AC:

970

AN:

39084

American (AMR)

AF:

0.00695

AC:

105

AN:

15106

Ashkenazi Jewish (ASJ)

AF:

0.00290

AC:

AN:

3448

East Asian (EAS)

AF:

0.0144

AC:

AN:

4940

South Asian (SAS)

AF:

0.00419

AC:

AN:

4770

European-Finnish (FIN)

AF:

0.00918

AC:

AN:

10134

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00114

AC:

AN:

67430

Other (OTH)

AF:

0.00480

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

Heterozygous variant carriers

111

167

222

278

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0106

Hom.:

Bravo

AF:

0.0189

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Dec 31, 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

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 27, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

-0.81

CADD

Benign

4.9

(source)

DANN

Benign

0.72

PhyloP100

0.24

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.8

Mutation Taster

=74/26

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000028

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over