1-1041648-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_198576.4(AGRN):c.1123G>T(p.Ala375Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00657 in 1,611,148 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A375T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0052 ( 2 hom., cov: 31)

Exomes 𝑓: 0.0067 ( 36 hom. )

Consequence

AGRN
NM_198576.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 1.49

Publications

13 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=0.0054303408).

BP6

Variant 1-1041648-G-T is Benign according to our data. Variant chr1-1041648-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 263158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00518 (788/152180) while in subpopulation NFE AF = 0.00694 (472/67966). AF 95% confidence interval is 0.00643. There are 2 homozygotes in GnomAd4. There are 341 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4 link	c.1123G>T	p.Ala375Ser	missense_variant	Exon 6 of 36	ENST00000379370.7	NP_940978.2	O00468-6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AGRN	ENST00000379370.7 link	c.1123G>T	p.Ala375Ser	missense_variant	Exon 6 of 36	1	NM_198576.4	ENSP00000368678.2	O00468-6
AGRN	ENST00000651234.1 link	c.808G>T	p.Ala270Ser	missense_variant	Exon 5 of 38			ENSP00000499046.1	A0A494C1I6
AGRN	ENST00000652369.2 link	c.808G>T	p.Ala270Ser	missense_variant	Exon 5 of 35			ENSP00000498543.1	A0A494C0G5
AGRN	ENST00000620552.4 link	c.709G>T	p.Ala237Ser	missense_variant	Exon 6 of 39	5		ENSP00000484607.1	A0A087X208

Frequencies

GnomAD3 genomes

AF:

0.00518

AC:

787

AN:

152064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00147

Gnomad AMI

AF:

0.0802

Gnomad AMR

AF:

0.00622

Gnomad ASJ

AF:

0.00893

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00226

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00694

Gnomad OTH

AF:

0.00765

GnomAD2 exomes

AF:

0.00493

AC:

1175

AN:

238246

AF XY:

0.00520

show subpopulations

Gnomad AFR exome

AF:

0.00113

Gnomad AMR exome

AF:

0.00388

Gnomad ASJ exome

AF:

0.0121

Gnomad EAS exome

AF:

0.0000564

Gnomad FIN exome

AF:

0.00330

Gnomad NFE exome

AF:

0.00699

Gnomad OTH exome

AF:

0.00561

GnomAD4 exome

AF:

0.00671

AC:

9794

AN:

1458968

Hom.:

Cov.:

AF XY:

0.00666

AC XY:

4836

AN XY:

725714

show subpopulations

African (AFR)

AF:

0.00147

AC:

AN:

33434

American (AMR)

AF:

0.00412

AC:

184

AN:

44648

Ashkenazi Jewish (ASJ)

AF:

0.0129

AC:

336

AN:

26064

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39656

South Asian (SAS)

AF:

0.00254

AC:

219

AN:

86176

European-Finnish (FIN)

AF:

0.00313

AC:

162

AN:

51828

Middle Eastern (MID)

AF:

0.0106

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.00752

AC:

8356

AN:

1111144

Other (OTH)

AF:

0.00707

AC:

426

AN:

60276

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

691

1381

2072

2762

3453

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00518

AC:

788

AN:

152180

Hom.:

Cov.:

AF XY:

0.00458

AC XY:

341

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.00147

AC:

AN:

41544

American (AMR)

AF:

0.00621

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00893

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5156

South Asian (SAS)

AF:

0.00187

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00226

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00694

AC:

472

AN:

67966

Other (OTH)

AF:

0.00757

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

140

186

233

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00647

Hom.:

Bravo

AF:

0.00574

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.000945

AC:

ESP6500EA

AF:

0.00706

AC:

ExAC

AF:

0.00466

AC:

560

Asia WGS

AF:

0.00116

AC:

AN:

3474

EpiCase

AF:

0.00834

EpiControl

AF:

0.00818

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Aug 30, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27378695) -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

AGRN: BS2 -

Dec 30, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 20, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

Feb 02, 2017

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 14, 2015

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Congenital myasthenic syndrome 8

Benign:2

Oct 15, 2018

SIB Swiss Institute of Bioinformatics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

This variant is interpreted as Benign, for Myasthenic syndrome, congenital, 8, autosomal recessive. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder. BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. -

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_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Benign

-0.062

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.22

LIST_S2

Uncertain

0.89

D;D

MetaRNN

Benign

0.0054

T;T

MetaSVM

Benign

-0.58

MutationAssessor

Benign

1.6

L;.

PhyloP100

1.5

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.1

N;.

REVEL

Benign

0.27

Sift

Uncertain

0.022

D;.

Sift4G

Benign

0.42

T;T

Vest4

0.46

MVP

0.71

MPC

0.94

ClinPred

0.023

GERP RS

4.7

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

gMVP

0.23

Mutation Taster

=96/4

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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1-1041648-G-T

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