1-1051762-C-T

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.5598C>T(p.Thr1866Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00593 in 1,613,892 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0069 ( 5 hom., cov: 34)

Exomes 𝑓: 0.0058 ( 28 hom. )

Consequence

AGRN
NM_198576.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -1.57

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 (REVEL=0.003).

BP6

Variant 1-1051762-C-T is Benign according to our data. Variant chr1-1051762-C-T is described in ClinVar as Benign. ClinVar VariationId is 128316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.57 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00685 (1044/152350) while in subpopulation AFR AF = 0.011 (457/41586). AF 95% confidence interval is 0.0102. There are 5 homozygotes in GnomAd4. There are 489 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4 link	c.5598C>T	p.Thr1866Thr	synonymous_variant	Exon 33 of 36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7 link	c.5598C>T	p.Thr1866Thr	synonymous_variant	Exon 33 of 36	1	NM_198576.4	ENSP00000368678.2

Frequencies

GnomAD3 genomes

AF:

0.00683

AC:

1039

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0109

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.00405

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00434

Gnomad FIN

AF:

0.000658

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00691

Gnomad OTH

AF:

0.00813

GnomAD2 exomes

AF:

0.00493

AC:

1235

AN:

250732

AF XY:

0.00481

show subpopulations

Gnomad AFR exome

AF:

0.0109

Gnomad AMR exome

AF:

0.00281

Gnomad ASJ exome

AF:

0.000498

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00120

Gnomad NFE exome

AF:

0.00736

Gnomad OTH exome

AF:

0.00474

GnomAD4 exome

AF:

0.00583

AC:

8527

AN:

1461542

Hom.:

Cov.:

AF XY:

0.00574

AC XY:

4177

AN XY:

727082

show subpopulations

African (AFR)

AF:

0.0111

AC:

370

AN:

33478

American (AMR)

AF:

0.00309

AC:

138

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.000804

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00299

AC:

258

AN:

86256

European-Finnish (FIN)

AF:

0.00132

AC:

AN:

53150

Middle Eastern (MID)

AF:

0.00555

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00659

AC:

7331

AN:

1111958

Other (OTH)

AF:

0.00508

AC:

307

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

555

1110

1666

2221

2776

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

262

524

786

1048

1310

<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:

0.00685

AC:

1044

AN:

152350

Hom.:

Cov.:

AF XY:

0.00656

AC XY:

489

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.0110

AC:

457

AN:

41586

American (AMR)

AF:

0.00405

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00435

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000658

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00691

AC:

470

AN:

68018

Other (OTH)

AF:

0.00804

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

113

169

226

282

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:

0.00665

Hom.:

Bravo

AF:

0.00728

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.00894

EpiControl

AF:

0.00913

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 09, 2018

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. -

Mar 22, 2021

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

AGRN: BP4, BP7, BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Congenital myasthenic syndrome 8

Benign:1

Jan 22, 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

-0.82

CADD

Benign

0.017

(source)

DANN

Benign

0.72

PhyloP100

-1.6

Mutation Taster

=100/0

polymorphism

(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