1-1041249-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.804C>T(p.Ala268Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00845 in 1,496,312 control chromosomes in the GnomAD database, including 746 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A268A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.043 ( 410 hom., cov: 31)

Exomes 𝑓: 0.0046 ( 336 hom. )

Consequence

AGRN
NM_198576.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0480

Publications

1 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=-0.49).

BP6

Variant 1-1041249-C-T is Benign according to our data. Variant chr1-1041249-C-T is described in ClinVar as [Benign]. Clinvar id is 128320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.048 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.141 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4 link	c.804C>T	p.Ala268Ala	synonymous_variant	Exon 5 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.804C>T	p.Ala268Ala	synonymous_variant	Exon 5 of 36	1	NM_198576.4	ENSP00000368678.2		O00468-6

Frequencies

GnomAD3 genomes

AF:

0.0428

AC:

6498

AN:

151798

Hom.:

410

Cov.:

show subpopulations

Gnomad AFR

AF:

0.144

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0226

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00152

Gnomad OTH

AF:

0.0360

GnomAD2 exomes

AF:

0.00599

AC:

605

AN:

100992

AF XY:

0.00504

show subpopulations

Gnomad AFR exome

AF:

0.152

Gnomad AMR exome

AF:

0.0117

Gnomad ASJ exome

AF:

0.00143

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000192

Gnomad NFE exome

AF:

0.00147

Gnomad OTH exome

AF:

0.00916

GnomAD4 exome

AF:

0.00456

AC:

6126

AN:

1344406

Hom.:

336

Cov.:

AF XY:

0.00415

AC XY:

2751

AN XY:

663606

show subpopulations

African (AFR)

AF:

0.144

AC:

3862

AN:

26762

American (AMR)

AF:

0.0133

AC:

419

AN:

31466

Ashkenazi Jewish (ASJ)

AF:

0.00191

AC:

AN:

23514

East Asian (EAS)

AF:

0.00

AC:

AN:

31166

South Asian (SAS)

AF:

0.000633

AC:

AN:

75838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33230

Middle Eastern (MID)

AF:

0.0145

AC:

AN:

5444

European-Non Finnish (NFE)

AF:

0.000920

AC:

976

AN:

1061324

Other (OTH)

AF:

0.0125

AC:

697

AN:

55662

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

305

609

914

1218

1523

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0429

AC:

6512

AN:

151906

Hom.:

410

Cov.:

AF XY:

0.0412

AC XY:

3056

AN XY:

74262

show subpopulations

African (AFR)

AF:

0.144

AC:

5972

AN:

41452

American (AMR)

AF:

0.0225

AC:

344

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000828

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10514

Middle Eastern (MID)

AF:

0.0137

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00152

AC:

103

AN:

67888

Other (OTH)

AF:

0.0356

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

292

584

875

1167

1459

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0279

Hom.:

Bravo

AF:

0.0498

ClinVar

Significance: Benign

Submissions summary: Benign:5

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

- -

Sep 20, 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. -

Oct 29, 2024

Athena Diagnostics

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

- -

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

BayesDel_noAF

Benign

-0.49

CADD

Benign

7.7

(source)

DANN

Benign

0.96

PhyloP100

-0.048

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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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1-1041249-C-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