1-1048922-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.4161T>C(p.Thr1387Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.567 in 1,556,060 control chromosomes in the GnomAD database, including 255,662 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.50 ( 20796 hom., cov: 27)

Exomes 𝑓: 0.57 ( 234866 hom. )

Consequence

AGRN
NM_198576.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.25

Publications

14 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=-0.92).

BP6

Variant 1-1048922-T-C is Benign according to our data. Variant chr1-1048922-T-C is described in ClinVar as Benign. ClinVar VariationId is 128307.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.25 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.798 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4 link	c.4161T>C	p.Thr1387Thr	synonymous_variant	Exon 24 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.4161T>C	p.Thr1387Thr	synonymous_variant	Exon 24 of 36	1	NM_198576.4	ENSP00000368678.2

Frequencies

GnomAD3 genomes

AF:

0.504

AC:

76215

AN:

151176

Hom.:

20786

Cov.:

show subpopulations

Gnomad AFR

AF:

0.292

Gnomad AMI

AF:

0.597

Gnomad AMR

AF:

0.647

Gnomad ASJ

AF:

0.566

Gnomad EAS

AF:

0.818

Gnomad SAS

AF:

0.567

Gnomad FIN

AF:

0.538

Gnomad MID

AF:

0.516

Gnomad NFE

AF:

0.562

Gnomad OTH

AF:

0.513

GnomAD2 exomes

AF:

0.588

AC:

98515

AN:

167448

AF XY:

0.586

show subpopulations

Gnomad AFR exome

AF:

0.273

Gnomad AMR exome

AF:

0.705

Gnomad ASJ exome

AF:

0.564

Gnomad EAS exome

AF:

0.820

Gnomad FIN exome

AF:

0.542

Gnomad NFE exome

AF:

0.565

Gnomad OTH exome

AF:

0.572

GnomAD4 exome

AF:

0.574

AC:

806482

AN:

1404778

Hom.:

234866

Cov.:

AF XY:

0.573

AC XY:

397526

AN XY:

693336

show subpopulations

African (AFR)

AF:

0.275

AC:

8833

AN:

32062

American (AMR)

AF:

0.694

AC:

26203

AN:

37734

Ashkenazi Jewish (ASJ)

AF:

0.564

AC:

14208

AN:

25202

East Asian (EAS)

AF:

0.832

AC:

30547

AN:

36698

South Asian (SAS)

AF:

0.559

AC:

44643

AN:

79840

European-Finnish (FIN)

AF:

0.542

AC:

25818

AN:

47636

Middle Eastern (MID)

AF:

0.550

AC:

2293

AN:

4172

European-Non Finnish (NFE)

AF:

0.573

AC:

621231

AN:

1083392

Other (OTH)

AF:

0.563

AC:

32706

AN:

58042

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

19114

38228

57342

76456

95570

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17470

34940

52410

69880

87350

<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:

0.504

AC:

76258

AN:

151282

Hom.:

20796

Cov.:

AF XY:

0.509

AC XY:

37606

AN XY:

73906

show subpopulations

African (AFR)

AF:

0.292

AC:

12026

AN:

41120

American (AMR)

AF:

0.647

AC:

9859

AN:

15236

Ashkenazi Jewish (ASJ)

AF:

0.566

AC:

1957

AN:

3458

East Asian (EAS)

AF:

0.818

AC:

4183

AN:

5112

South Asian (SAS)

AF:

0.567

AC:

2717

AN:

4794

European-Finnish (FIN)

AF:

0.538

AC:

5637

AN:

10472

Middle Eastern (MID)

AF:

0.524

AC:

154

AN:

294

European-Non Finnish (NFE)

AF:

0.562

AC:

38097

AN:

67788

Other (OTH)

AF:

0.517

AC:

1085

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

Heterozygous variant carriers

1722

3444

5166

6888

8610

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

674

1348

2022

2696

3370

<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:

0.552

Hom.:

8268

Bravo

AF:

0.503

Asia WGS

AF:

0.675

AC:

2344

AN:

3470

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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.

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

-0.92

CADD

Benign

0.24

(source)

DANN

Benign

0.25

PhyloP100

-1.2

Mutation Taster

=99/1

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