rs147681220

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.5223C>T(p.Gly1741Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00556 in 1,592,094 control chromosomes in the GnomAD database, including 112 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0077 ( 25 hom., cov: 33)

Exomes 𝑓: 0.0053 ( 87 hom. )

Consequence

AGRN
NM_198576.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.25

Publications

0 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=-0.67).

BP6

Variant 1-1050807-C-T is Benign according to our data. Variant chr1-1050807-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 474144.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.25 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00774 (1178/152182) while in subpopulation NFE AF = 0.00546 (371/67974). AF 95% confidence interval is 0.005. There are 25 homozygotes in GnomAd4. There are 761 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 25 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4 link	c.5223C>T	p.Gly1741Gly	synonymous_variant	Exon 30 of 36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
AGRN	ENST00000379370.7 link	c.5223C>T	p.Gly1741Gly	synonymous_variant	Exon 30 of 36	1	NM_198576.4	ENSP00000368678.2
AGRN	ENST00000651234.1 link	c.4908C>T	p.Gly1636Gly	synonymous_variant	Exon 29 of 38			ENSP00000499046.1
AGRN	ENST00000652369.2 link	c.4908C>T	p.Gly1636Gly	synonymous_variant	Exon 29 of 35			ENSP00000498543.1
AGRN	ENST00000620552.4 link	c.4809C>T	p.Gly1603Gly	synonymous_variant	Exon 30 of 39	5		ENSP00000484607.1

Frequencies

GnomAD3 genomes

AF:

0.00775

AC:

1178

AN:

152064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000676

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.00262

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00309

Gnomad SAS

AF:

0.00477

Gnomad FIN

AF:

0.0647

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00546

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.00793

AC:

1680

AN:

211816

AF XY:

0.00775

show subpopulations

Gnomad AFR exome

AF:

0.000534

Gnomad AMR exome

AF:

0.00486

Gnomad ASJ exome

AF:

0.000323

Gnomad EAS exome

AF:

0.000489

Gnomad FIN exome

AF:

0.0552

Gnomad NFE exome

AF:

0.00592

Gnomad OTH exome

AF:

0.0100

GnomAD4 exome

AF:

0.00533

AC:

7681

AN:

1439912

Hom.:

Cov.:

AF XY:

0.00535

AC XY:

3827

AN XY:

715272

show subpopulations

African (AFR)

AF:

0.000511

AC:

AN:

33238

American (AMR)

AF:

0.00501

AC:

213

AN:

42490

Ashkenazi Jewish (ASJ)

AF:

0.000816

AC:

AN:

25750

East Asian (EAS)

AF:

0.000308

AC:

AN:

39024

South Asian (SAS)

AF:

0.00481

AC:

404

AN:

83988

European-Finnish (FIN)

AF:

0.0522

AC:

2390

AN:

45822

Middle Eastern (MID)

AF:

0.00366

AC:

AN:

4366

European-Non Finnish (NFE)

AF:

0.00389

AC:

4301

AN:

1105654

Other (OTH)

AF:

0.00515

AC:

307

AN:

59580

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

431

862

1292

1723

2154

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

140

280

420

560

700

<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:

0.00774

AC:

1178

AN:

152182

Hom.:

Cov.:

AF XY:

0.0102

AC XY:

761

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.000674

AC:

AN:

41516

American (AMR)

AF:

0.00262

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00310

AC:

AN:

5164

South Asian (SAS)

AF:

0.00477

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0647

AC:

687

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00546

AC:

371

AN:

67974

Other (OTH)

AF:

0.00379

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

120

179

239

299

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:

0.00602

Hom.:

Bravo

AF:

0.00272

Asia WGS

AF:

0.00635

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

AGRN: BP4, BP7, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Sep 02, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

AGRN-related disorder

Benign:1

May 02, 2024

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Congenital myasthenic syndrome 8

Benign:1

Jan 31, 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

-0.67

CADD

Benign

0.27

(source)

DANN

Benign

0.74

PhyloP100

-1.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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