NM_198576.4:c.4839C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PP3_ModerateBP6_Very_StrongBS1BS2

The NM_198576.4(AGRN):c.4839C>T(p.Cys1613Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00422 in 1,513,062 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0030 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0044 ( 21 hom. )

Consequence

AGRN
NM_198576.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.325

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 -14 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant 1-1049997-C-T is Benign according to our data. Variant chr1-1049997-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 263189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00296 (429/144898) while in subpopulation NFE AF = 0.00435 (288/66144). AF 95% confidence interval is 0.00394. There are 0 homozygotes in GnomAd4. There are 212 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 21 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4 link	c.4839C>T	p.Cys1613Cys	synonymous_variant	Exon 27 of 36	ENST00000379370.7	NP_940978.2	O00468-6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AGRN	ENST00000379370.7 link	c.4839C>T	p.Cys1613Cys	synonymous_variant	Exon 27 of 36	1	NM_198576.4	ENSP00000368678.2	O00468-6
AGRN	ENST00000651234.1 link	c.4524C>T	p.Cys1508Cys	synonymous_variant	Exon 26 of 38			ENSP00000499046.1	A0A494C1I6
AGRN	ENST00000652369.2 link	c.4524C>T	p.Cys1508Cys	synonymous_variant	Exon 26 of 35			ENSP00000498543.1	A0A494C0G5
AGRN	ENST00000620552.4 link	c.4425C>T	p.Cys1475Cys	synonymous_variant	Exon 27 of 39	5		ENSP00000484607.1	A0A087X208

Frequencies

GnomAD3 genomes

AF:

0.00296

AC:

429

AN:

144784

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000995

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00373

Gnomad ASJ

AF:

0.000592

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000479

Gnomad FIN

AF:

0.00391

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00435

Gnomad OTH

AF:

0.00294

GnomAD2 exomes

AF:

0.00273

AC:

647

AN:

237116

AF XY:

0.00268

show subpopulations

Gnomad AFR exome

AF:

0.000974

Gnomad AMR exome

AF:

0.00129

Gnomad ASJ exome

AF:

0.000415

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00541

Gnomad NFE exome

AF:

0.00427

Gnomad OTH exome

AF:

0.00223

GnomAD4 exome

AF:

0.00436

AC:

5961

AN:

1368164

Hom.:

Cov.:

AF XY:

0.00420

AC XY:

2856

AN XY:

680044

show subpopulations

African (AFR)

AF:

0.000700

AC:

AN:

28564

American (AMR)

AF:

0.00155

AC:

AN:

42062

Ashkenazi Jewish (ASJ)

AF:

0.000442

AC:

AN:

22628

East Asian (EAS)

AF:

0.00

AC:

AN:

31450

South Asian (SAS)

AF:

0.000539

AC:

AN:

85366

European-Finnish (FIN)

AF:

0.00485

AC:

212

AN:

43702

Middle Eastern (MID)

AF:

0.000191

AC:

AN:

5244

European-Non Finnish (NFE)

AF:

0.00517

AC:

5452

AN:

1055402

Other (OTH)

AF:

0.00288

AC:

155

AN:

53746

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

358

715

1073

1430

1788

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

220

440

660

880

1100

<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:

0.00296

AC:

429

AN:

144898

Hom.:

Cov.:

AF XY:

0.00300

AC XY:

212

AN XY:

70584

show subpopulations

African (AFR)

AF:

0.000993

AC:

AN:

39294

American (AMR)

AF:

0.00372

AC:

AN:

14790

Ashkenazi Jewish (ASJ)

AF:

0.000592

AC:

AN:

3380

East Asian (EAS)

AF:

0.00

AC:

AN:

4388

South Asian (SAS)

AF:

0.000478

AC:

AN:

4186

European-Finnish (FIN)

AF:

0.00391

AC:

AN:

9474

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00435

AC:

288

AN:

66144

Other (OTH)

AF:

0.00291

AC:

AN:

2060

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

107

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00349

Hom.:

Bravo

AF:

0.00258

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00463

EpiControl

AF:

0.00339

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

Oct 09, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 27, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

AGRN: PP3, BS2 -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Congenital myasthenic syndrome 8

Benign:1

Feb 01, 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

-0.52

CADD

Benign

(source)

DANN

Benign

0.44

PhyloP100

-0.33

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.5

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.98

Position offset: -2

DS_DL_spliceai

0.60

Position offset: 40

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