1-1049886-C-T

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.4745-17C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.54 in 1,611,140 control chromosomes in the GnomAD database, including 244,064 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.45 ( 18227 hom., cov: 31)

Exomes 𝑓: 0.55 ( 225837 hom. )

Consequence

AGRN
NM_198576.4 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.75

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 (BayesDel_noAF=-0.86).

BP6

Variant 1-1049886-C-T is Benign according to our data. Variant chr1-1049886-C-T is described in CliVar as Benign. Clinvar id is 263188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1049886-C-T is described in CliVar as Benign. Clinvar id is 263188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1049886-C-T is described in CliVar as Benign. Clinvar id is 263188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1049886-C-T is described in CliVar as Benign. Clinvar id is 263188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1049886-C-T is described in CliVar as Benign. Clinvar id is 263188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1049886-C-T is described in CliVar as Benign. Clinvar id is 263188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1049886-C-T is described in CliVar as Benign. Clinvar id is 263188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1049886-C-T is described in CliVar as Benign. Clinvar id is 263188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.788 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4 link	c.4745-17C>T		intron_variant	Intron 26 of 35	ENST00000379370.7	NP_940978.2	O00468-6

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
AGRN	ENST00000379370.7 link	c.4745-17C>T	intron_variant	Intron 26 of 35	1	NM_198576.4	ENSP00000368678.2	O00468-6
AGRN	ENST00000651234.1 link	c.4430-17C>T	intron_variant	Intron 25 of 37			ENSP00000499046.1	A0A494C1I6
AGRN	ENST00000652369.2 link	c.4430-17C>T	intron_variant	Intron 25 of 34			ENSP00000498543.1	A0A494C0G5
AGRN	ENST00000620552.4 link	c.4331-17C>T	intron_variant	Intron 26 of 38	5		ENSP00000484607.1	A0A087X208

Frequencies

GnomAD3 genomes

AF:

0.452

AC:

68428

AN:

151336

Hom.:

18221

Cov.:

show subpopulations

Gnomad AFR

AF:

0.161

Gnomad AMI

AF:

0.595

Gnomad AMR

AF:

0.624

Gnomad ASJ

AF:

0.544

Gnomad EAS

AF:

0.809

Gnomad SAS

AF:

0.549

Gnomad FIN

AF:

0.525

Gnomad MID

AF:

0.506

Gnomad NFE

AF:

0.537

Gnomad OTH

AF:

0.480

GnomAD2 exomes

AF:

0.557

AC:

133962

AN:

240300

AF XY:

0.556

show subpopulations

Gnomad AFR exome

AF:

0.148

Gnomad AMR exome

AF:

0.711

Gnomad ASJ exome

AF:

0.544

Gnomad EAS exome

AF:

0.810

Gnomad FIN exome

AF:

0.529

Gnomad NFE exome

AF:

0.535

Gnomad OTH exome

AF:

0.542

GnomAD4 exome

AF:

0.550

AC:

802180

AN:

1459684

Hom.:

225837

Cov.:

AF XY:

0.549

AC XY:

398741

AN XY:

726164

show subpopulations

African (AFR)

AF:

0.142

AC:

4729

AN:

33414

American (AMR)

AF:

0.697

AC:

31136

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.543

AC:

14168

AN:

26100

East Asian (EAS)

AF:

0.825

AC:

32739

AN:

39686

South Asian (SAS)

AF:

0.545

AC:

46964

AN:

86236

European-Finnish (FIN)

AF:

0.529

AC:

27444

AN:

51842

Middle Eastern (MID)

AF:

0.517

AC:

2970

AN:

5750

European-Non Finnish (NFE)

AF:

0.549

AC:

609963

AN:

1111646

Other (OTH)

AF:

0.531

AC:

32067

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

23703

47406

71109

94812

118515

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17254

34508

51762

69016

86270

<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:

0.452

AC:

68450

AN:

151456

Hom.:

18227

Cov.:

AF XY:

0.458

AC XY:

33856

AN XY:

73966

show subpopulations

African (AFR)

AF:

0.160

AC:

6616

AN:

41228

American (AMR)

AF:

0.625

AC:

9549

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.544

AC:

1886

AN:

3464

East Asian (EAS)

AF:

0.809

AC:

4129

AN:

5106

South Asian (SAS)

AF:

0.548

AC:

2630

AN:

4800

European-Finnish (FIN)

AF:

0.525

AC:

5518

AN:

10506

Middle Eastern (MID)

AF:

0.510

AC:

149

AN:

292

European-Non Finnish (NFE)

AF:

0.537

AC:

36413

AN:

67772

Other (OTH)

AF:

0.485

AC:

1017

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1638

3277

4915

6554

8192

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

610

1220

1830

2440

3050

<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:

0.506

Hom.:

4369

Bravo

AF:

0.448

Asia WGS

AF:

0.646

AC:

2246

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Congenital myasthenic syndrome 8

Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

-0.86

CADD

Benign

0.76

(source)

DANN

Benign

0.44

PhyloP100

-1.7

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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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