chr1-1055000-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000461111.1(AGRN):n.2273C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.297 in 1,546,620 control chromosomes in the GnomAD database, including 71,020 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.35 ( 10257 hom., cov: 35)

Exomes 𝑓: 0.29 ( 60763 hom. )

Consequence

AGRN
ENST00000461111.1 non_coding_transcript_exon

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.413

Publications

9 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:

ENSG00000242590 (HGNC:):

ENSG00000242590 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.502 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4 link	c.*19C>T		3_prime_UTR_variant	Exon 36 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.*19C>T		3_prime_UTR_variant	Exon 36 of 36	1	NM_198576.4	ENSP00000368678.2		O00468-6

Frequencies

GnomAD3 genomes

AF:

0.351

AC:

53401

AN:

152020

Hom.:

10237

Cov.:

show subpopulations

Gnomad AFR

AF:

0.507

Gnomad AMI

AF:

0.327

Gnomad AMR

AF:

0.254

Gnomad ASJ

AF:

0.307

Gnomad EAS

AF:

0.183

Gnomad SAS

AF:

0.319

Gnomad FIN

AF:

0.361

Gnomad MID

AF:

0.342

Gnomad NFE

AF:

0.295

Gnomad OTH

AF:

0.347

GnomAD2 exomes

AF:

0.291

AC:

43425

AN:

149096

AF XY:

0.292

show subpopulations

Gnomad AFR exome

AF:

0.523

Gnomad AMR exome

AF:

0.214

Gnomad ASJ exome

AF:

0.311

Gnomad EAS exome

AF:

0.179

Gnomad FIN exome

AF:

0.351

Gnomad NFE exome

AF:

0.292

Gnomad OTH exome

AF:

0.299

GnomAD4 exome

AF:

0.291

AC:

406267

AN:

1394482

Hom.:

60763

Cov.:

AF XY:

0.292

AC XY:

200824

AN XY:

687958

show subpopulations

African (AFR)

AF:

0.513

AC:

16173

AN:

31550

American (AMR)

AF:

0.221

AC:

7904

AN:

35732

Ashkenazi Jewish (ASJ)

AF:

0.309

AC:

7775

AN:

25160

East Asian (EAS)

AF:

0.167

AC:

5969

AN:

35730

South Asian (SAS)

AF:

0.311

AC:

24602

AN:

79194

European-Finnish (FIN)

AF:

0.347

AC:

15830

AN:

45570

Middle Eastern (MID)

AF:

0.286

AC:

1456

AN:

5088

European-Non Finnish (NFE)

AF:

0.286

AC:

308995

AN:

1078574

Other (OTH)

AF:

0.303

AC:

17563

AN:

57884

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

16407

32813

49220

65626

82033

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.351

AC:

53463

AN:

152138

Hom.:

10257

Cov.:

AF XY:

0.351

AC XY:

26083

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.508

AC:

21068

AN:

41510

American (AMR)

AF:

0.253

AC:

3877

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.307

AC:

1067

AN:

3472

East Asian (EAS)

AF:

0.183

AC:

947

AN:

5170

South Asian (SAS)

AF:

0.318

AC:

1535

AN:

4824

European-Finnish (FIN)

AF:

0.361

AC:

3824

AN:

10586

Middle Eastern (MID)

AF:

0.333

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.295

AC:

20022

AN:

67962

Other (OTH)

AF:

0.345

AC:

727

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1754

3508

5262

7016

8770

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.308

Hom.:

2925

Bravo

AF:

0.349

Asia WGS

AF:

0.262

AC:

910

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

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

- -

Feb 01, 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. -

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

Apr 11, 2023

Genome-Nilou Lab

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

-0.93

CADD

Benign

1.1

(source)

DANN

Benign

0.61

PhyloP100

-0.41

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

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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chr1-1055000-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