chr1-1050520-C-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.5070C>T(p.Phe1690Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0132 in 1,612,818 control chromosomes in the GnomAD database, including 722 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.042 ( 372 hom., cov: 33)

Exomes 𝑓: 0.010 ( 350 hom. )

Consequence

AGRN
NM_198576.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.29

Publications

5 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=-0.49).

BP6

Variant 1-1050520-C-T is Benign according to our data. Variant chr1-1050520-C-T is described in ClinVar as Benign. ClinVar VariationId is 128313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.29 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4 link	c.5070C>T	p.Phe1690Phe	synonymous_variant	Exon 29 of 36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
AGRN	ENST00000379370.7 link	c.5070C>T	p.Phe1690Phe	synonymous_variant	Exon 29 of 36	1	NM_198576.4	ENSP00000368678.2
AGRN	ENST00000651234.1 link	c.4755C>T	p.Phe1585Phe	synonymous_variant	Exon 28 of 38			ENSP00000499046.1
AGRN	ENST00000652369.2 link	c.4755C>T	p.Phe1585Phe	synonymous_variant	Exon 28 of 35			ENSP00000498543.1
AGRN	ENST00000620552.4 link	c.4656C>T	p.Phe1552Phe	synonymous_variant	Exon 29 of 39	5		ENSP00000484607.1

Frequencies

GnomAD3 genomes

AF:

0.0417

AC:

6345

AN:

152100

Hom.:

369

Cov.:

show subpopulations

Gnomad AFR

AF:

0.130

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.0188

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00538

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00813

Gnomad OTH

AF:

0.0330

GnomAD2 exomes

AF:

0.0147

AC:

3658

AN:

248502

AF XY:

0.0121

show subpopulations

Gnomad AFR exome

AF:

0.131

Gnomad AMR exome

AF:

0.0113

Gnomad ASJ exome

AF:

0.00361

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00121

Gnomad NFE exome

AF:

0.00858

Gnomad OTH exome

AF:

0.0125

GnomAD4 exome

AF:

0.0102

AC:

14882

AN:

1460600

Hom.:

350

Cov.:

AF XY:

0.00974

AC XY:

7075

AN XY:

726644

show subpopulations

African (AFR)

AF:

0.135

AC:

4518

AN:

33478

American (AMR)

AF:

0.0125

AC:

559

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00368

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00364

AC:

314

AN:

86250

European-Finnish (FIN)

AF:

0.00134

AC:

AN:

52348

Middle Eastern (MID)

AF:

0.0172

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00744

AC:

8269

AN:

1111890

Other (OTH)

AF:

0.0159

AC:

957

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

985

1970

2956

3941

4926

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

370

740

1110

1480

1850

<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:

0.0418

AC:

6366

AN:

152218

Hom.:

372

Cov.:

AF XY:

0.0403

AC XY:

3003

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.130

AC:

5403

AN:

41514

American (AMR)

AF:

0.0187

AC:

286

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00538

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000659

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00813

AC:

553

AN:

67992

Other (OTH)

AF:

0.0326

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

294

587

881

1174

1468

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

186

248

310

<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:

0.0227

Hom.:

132

Bravo

AF:

0.0471

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.00992

EpiControl

AF:

0.0109

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Oct 29, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 26, 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

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

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

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

-0.49

CADD

Benign

0.49

(source)

DANN

Benign

0.86

PhyloP100

-1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=99/1

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

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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