1-1047614-T-C

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.3558T>C(p.Phe1186Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.907 in 1,612,940 control chromosomes in the GnomAD database, including 669,418 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.82 ( 53400 hom., cov: 35)

Exomes 𝑓: 0.92 ( 616018 hom. )

Consequence

AGRN
NM_198576.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.15

Publications

17 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=-0.63).

BP6

Variant 1-1047614-T-C is Benign according to our data. Variant chr1-1047614-T-C is described in ClinVar as Benign. ClinVar VariationId is 128302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.15 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4 link	c.3558T>C	p.Phe1186Phe	synonymous_variant	Exon 21 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.3558T>C	p.Phe1186Phe	synonymous_variant	Exon 21 of 36	1	NM_198576.4	ENSP00000368678.2

Frequencies

GnomAD3 genomes

AF:

0.820

AC:

124694

AN:

152140

Hom.:

53403

Cov.:

show subpopulations

Gnomad AFR

AF:

0.538

Gnomad AMI

AF:

0.986

Gnomad AMR

AF:

0.896

Gnomad ASJ

AF:

0.924

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.957

Gnomad FIN

AF:

0.958

Gnomad MID

AF:

0.879

Gnomad NFE

AF:

0.920

Gnomad OTH

AF:

0.846

GnomAD2 exomes

AF:

0.908

AC:

227622

AN:

250598

AF XY:

0.916

show subpopulations

Gnomad AFR exome

AF:

0.525

Gnomad AMR exome

AF:

0.939

Gnomad ASJ exome

AF:

0.923

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

0.953

Gnomad NFE exome

AF:

0.917

Gnomad OTH exome

AF:

0.908

GnomAD4 exome

AF:

0.916

AC:

1337920

AN:

1460682

Hom.:

616018

Cov.:

AF XY:

0.918

AC XY:

667056

AN XY:

726632

show subpopulations

African (AFR)

AF:

0.516

AC:

17271

AN:

33480

American (AMR)

AF:

0.933

AC:

41707

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.920

AC:

24044

AN:

26136

East Asian (EAS)

AF:

1.00

AC:

39685

AN:

39700

South Asian (SAS)

AF:

0.952

AC:

82130

AN:

86258

European-Finnish (FIN)

AF:

0.951

AC:

49677

AN:

52244

Middle Eastern (MID)

AF:

0.864

AC:

4986

AN:

5768

European-Non Finnish (NFE)

AF:

0.921

AC:

1024039

AN:

1111990

Other (OTH)

AF:

0.901

AC:

54381

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

7666

15332

22999

30665

38331

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21476

42952

64428

85904

107380

<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:

0.819

AC:

124724

AN:

152258

Hom.:

53400

Cov.:

AF XY:

0.825

AC XY:

61395

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.537

AC:

22307

AN:

41512

American (AMR)

AF:

0.896

AC:

13715

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.924

AC:

3207

AN:

3472

East Asian (EAS)

AF:

0.999

AC:

5174

AN:

5178

South Asian (SAS)

AF:

0.956

AC:

4621

AN:

4834

European-Finnish (FIN)

AF:

0.958

AC:

10178

AN:

10624

Middle Eastern (MID)

AF:

0.877

AC:

256

AN:

292

European-Non Finnish (NFE)

AF:

0.920

AC:

62575

AN:

68016

Other (OTH)

AF:

0.848

AC:

1792

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

947

1894

2840

3787

4734

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

858

1716

2574

3432

4290

<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:

0.878

Hom.:

34847

Bravo

AF:

0.800

Asia WGS

AF:

0.947

AC:

3292

AN:

3478

EpiCase

AF:

0.915

EpiControl

AF:

0.907

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PreventionGenetics, part of Exact Sciences

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 14, 2021

Genome-Nilou Lab

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

-0.63

CADD

Benign

6.6

(source)

DANN

Benign

0.32

PhyloP100

2.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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