rs142416636

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_198576.4(AGRN):c.3404A>G(p.Gln1135Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00958 in 1,605,086 control chromosomes in the GnomAD database, including 281 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0077 ( 26 hom., cov: 34)

Exomes 𝑓: 0.0098 ( 255 hom. )

Consequence

AGRN
NM_198576.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.00

Publications

12 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007086724).

BP6

Variant 1-1047342-A-G is Benign according to our data. Variant chr1-1047342-A-G is described in ClinVar as Benign. ClinVar VariationId is 128299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0518 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4 link	c.3404A>G	p.Gln1135Arg	missense_variant	Exon 20 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.3404A>G	p.Gln1135Arg	missense_variant	Exon 20 of 36	1	NM_198576.4	ENSP00000368678.2		O00468-6

Frequencies

GnomAD3 genomes

AF:

0.00775

AC:

1180

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00125

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00419

Gnomad ASJ

AF:

0.0288

Gnomad EAS

AF:

0.00482

Gnomad SAS

AF:

0.0573

Gnomad FIN

AF:

0.00367

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.00866

Gnomad OTH

AF:

0.0124

GnomAD2 exomes

AF:

0.0130

AC:

3174

AN:

243754

AF XY:

0.0159

show subpopulations

Gnomad AFR exome

AF:

0.00193

Gnomad AMR exome

AF:

0.00294

Gnomad ASJ exome

AF:

0.0286

Gnomad EAS exome

AF:

0.00395

Gnomad FIN exome

AF:

0.00346

Gnomad NFE exome

AF:

0.00819

Gnomad OTH exome

AF:

0.0139

GnomAD4 exome

AF:

0.00977

AC:

14198

AN:

1452758

Hom.:

255

Cov.:

AF XY:

0.0115

AC XY:

8280

AN XY:

722106

show subpopulations

African (AFR)

AF:

0.00127

AC:

AN:

33122

American (AMR)

AF:

0.00299

AC:

129

AN:

43168

Ashkenazi Jewish (ASJ)

AF:

0.0299

AC:

770

AN:

25716

East Asian (EAS)

AF:

0.00179

AC:

AN:

39608

South Asian (SAS)

AF:

0.0567

AC:

4824

AN:

85048

European-Finnish (FIN)

AF:

0.00439

AC:

229

AN:

52160

Middle Eastern (MID)

AF:

0.0307

AC:

176

AN:

5730

European-Non Finnish (NFE)

AF:

0.00648

AC:

7187

AN:

1108284

Other (OTH)

AF:

0.0129

AC:

770

AN:

59922

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

843

1685

2528

3370

4213

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

290

580

870

1160

1450

<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:

0.00773

AC:

1177

AN:

152328

Hom.:

Cov.:

AF XY:

0.00839

AC XY:

625

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.00125

AC:

AN:

41590

American (AMR)

AF:

0.00418

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0288

AC:

100

AN:

3472

East Asian (EAS)

AF:

0.00463

AC:

AN:

5178

South Asian (SAS)

AF:

0.0574

AC:

277

AN:

4826

European-Finnish (FIN)

AF:

0.00367

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00866

AC:

589

AN:

68006

Other (OTH)

AF:

0.0118

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

123

184

246

307

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.00857

Hom.:

Bravo

AF:

0.00612

TwinsUK

AF:

0.00620

AC:

ALSPAC

AF:

0.00856

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00744

AC:

ExAC

AF:

0.0140

AC:

1697

Asia WGS

AF:

0.0200

AC:

AN:

3478

EpiCase

AF:

0.0102

EpiControl

AF:

0.00765

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 21, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 31167812) -

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

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.84

T;T

MetaRNN

Benign

0.0071

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

M;.

PhyloP100

2.0

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.6

N;.

REVEL

Benign

0.19

Sift

Uncertain

0.012

D;.

Sift4G

Uncertain

0.0070

D;D

Vest4

0.52

MPC

0.59

ClinPred

0.013

GERP RS

4.2

gMVP

0.68

Mutation Taster

=93/7

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