1-1054900-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.6057C>T(p.Asp2019Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.682 in 1,549,936 control chromosomes in the GnomAD database, including 367,096 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.59 ( 28846 hom., cov: 34)

Exomes 𝑓: 0.69 ( 338250 hom. )

Consequence

AGRN
NM_198576.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.712

Publications

18 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:

ENSG00000242590 (HGNC:):

ENSG00000242590 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=-0.52).

BP6

Variant 1-1054900-C-T is Benign according to our data. Variant chr1-1054900-C-T is described in ClinVar as Benign. ClinVar VariationId is 128319.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.712 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.791 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4 link	c.6057C>T	p.Asp2019Asp	synonymous_variant	Exon 36 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.6057C>T	p.Asp2019Asp	synonymous_variant	Exon 36 of 36	1	NM_198576.4	ENSP00000368678.2		O00468-6

Frequencies

GnomAD3 genomes

AF:

0.591

AC:

89880

AN:

152000

Hom.:

28830

Cov.:

show subpopulations

Gnomad AFR

AF:

0.323

Gnomad AMI

AF:

0.673

Gnomad AMR

AF:

0.720

Gnomad ASJ

AF:

0.662

Gnomad EAS

AF:

0.812

Gnomad SAS

AF:

0.607

Gnomad FIN

AF:

0.634

Gnomad MID

AF:

0.639

Gnomad NFE

AF:

0.696

Gnomad OTH

AF:

0.600

GnomAD2 exomes

AF:

0.676

AC:

104123

AN:

153932

AF XY:

0.675

show subpopulations

Gnomad AFR exome

AF:

0.311

Gnomad AMR exome

AF:

0.772

Gnomad ASJ exome

AF:

0.658

Gnomad EAS exome

AF:

0.814

Gnomad FIN exome

AF:

0.641

Gnomad NFE exome

AF:

0.698

Gnomad OTH exome

AF:

0.676

GnomAD4 exome

AF:

0.692

AC:

967055

AN:

1397818

Hom.:

338250

Cov.:

AF XY:

0.690

AC XY:

475706

AN XY:

689810

show subpopulations

African (AFR)

AF:

0.308

AC:

9780

AN:

31770

American (AMR)

AF:

0.762

AC:

27531

AN:

36128

Ashkenazi Jewish (ASJ)

AF:

0.658

AC:

16565

AN:

25172

East Asian (EAS)

AF:

0.830

AC:

29822

AN:

35928

South Asian (SAS)

AF:

0.612

AC:

48541

AN:

79286

European-Finnish (FIN)

AF:

0.645

AC:

30503

AN:

47274

Middle Eastern (MID)

AF:

0.661

AC:

2851

AN:

4316

European-Non Finnish (NFE)

AF:

0.706

AC:

762723

AN:

1080050

Other (OTH)

AF:

0.669

AC:

38739

AN:

57894

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

20262

40524

60787

81049

101311

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19370

38740

58110

77480

96850

<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:

0.591

AC:

89927

AN:

152118

Hom.:

28846

Cov.:

AF XY:

0.592

AC XY:

44024

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.323

AC:

13380

AN:

41474

American (AMR)

AF:

0.720

AC:

11016

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.662

AC:

2299

AN:

3472

East Asian (EAS)

AF:

0.812

AC:

4207

AN:

5182

South Asian (SAS)

AF:

0.607

AC:

2928

AN:

4820

European-Finnish (FIN)

AF:

0.634

AC:

6727

AN:

10606

Middle Eastern (MID)

AF:

0.646

AC:

190

AN:

294

European-Non Finnish (NFE)

AF:

0.696

AC:

47297

AN:

67952

Other (OTH)

AF:

0.603

AC:

1273

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1719

3438

5157

6876

8595

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

742

1484

2226

2968

3710

<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:

0.658

Hom.:

12328

Bravo

AF:

0.588

Asia WGS

AF:

0.693

AC:

2411

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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

- -

Jan 19, 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. -

Congenital myasthenic syndrome 8

Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

0.36

(source)

DANN

Benign

0.77

PhyloP100

-0.71

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.5

Mutation Taster

=92/8

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