Genetic Variant AGRN:p.Thr258Ile (chr1-1041218-C-T) – ACMG Classification: Benign (-20 pts)

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.773C>T(p.Thr258Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00126 in 1,471,100 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0025 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0011 ( 14 hom. )

Consequence

AGRN
NM_198576.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 4.51

Publications

7 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: DEFINITIVE, STRONG Submitted by: ClinGen, 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=0.008708686).

BP6

Variant 1-1041218-C-T is Benign according to our data. Variant chr1-1041218-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 263204.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00247 (374/151220) while in subpopulation EAS AF = 0.0167 (85/5088). AF 95% confidence interval is 0.0138. There are 0 homozygotes in GnomAd4. There are 206 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 14 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198576.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AGRN	NM_198576.4	MANE Select	c.773C>T	p.Thr258Ile	missense	Exon 5 of 36	NP_940978.2
AGRN	NM_001305275.2		c.773C>T	p.Thr258Ile	missense	Exon 5 of 39	NP_001292204.1	O00468-1
AGRN	NM_001364727.2		c.458C>T	p.Thr153Ile	missense	Exon 4 of 36	NP_001351656.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AGRN	ENST00000379370.7	TSL:1 MANE Select	c.773C>T	p.Thr258Ile	missense	Exon 5 of 36	ENSP00000368678.2	O00468-6
AGRN	ENST00000651234.1		c.458C>T	p.Thr153Ile	missense	Exon 4 of 38	ENSP00000499046.1	A0A494C1I6
AGRN	ENST00000652369.2		c.458C>T	p.Thr153Ile	missense	Exon 4 of 35	ENSP00000498543.1	A0A494C0G5

Frequencies

GnomAD3 genomes

AF:

0.00247

AC:

373

AN:

151112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00153

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000789

Gnomad ASJ

AF:

0.00289

Gnomad EAS

AF:

0.0167

Gnomad SAS

AF:

0.00292

Gnomad FIN

AF:

0.0101

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00117

Gnomad OTH

AF:

0.00288

GnomAD2 exomes

AF:

0.00456

AC:

396

AN:

86804

AF XY:

0.00467

show subpopulations

Gnomad AFR exome

AF:

0.00332

Gnomad AMR exome

AF:

0.00144

Gnomad ASJ exome

AF:

0.00497

Gnomad EAS exome

AF:

0.0172

Gnomad FIN exome

AF:

0.0179

Gnomad NFE exome

AF:

0.00234

Gnomad OTH exome

AF:

0.00360

GnomAD4 exome

AF:

0.00112

AC:

1484

AN:

1319880

Hom.:

Cov.:

AF XY:

0.00113

AC XY:

734

AN XY:

651604

show subpopulations

African (AFR)

AF:

0.000986

AC:

AN:

26358

American (AMR)

AF:

0.000466

AC:

AN:

27900

Ashkenazi Jewish (ASJ)

AF:

0.00145

AC:

AN:

22696

East Asian (EAS)

AF:

0.0171

AC:

487

AN:

28398

South Asian (SAS)

AF:

0.000805

AC:

AN:

73248

European-Finnish (FIN)

AF:

0.0109

AC:

355

AN:

32618

Middle Eastern (MID)

AF:

0.00351

AC:

AN:

5128

European-Non Finnish (NFE)

AF:

0.000367

AC:

385

AN:

1049238

Other (OTH)

AF:

0.00199

AC:

108

AN:

54296

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

178

266

355

444

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.00247

AC:

374

AN:

151220

Hom.:

Cov.:

AF XY:

0.00279

AC XY:

206

AN XY:

73872

show subpopulations

African (AFR)

AF:

0.00152

AC:

AN:

41388

American (AMR)

AF:

0.000788

AC:

AN:

15228

Ashkenazi Jewish (ASJ)

AF:

0.00289

AC:

AN:

3464

East Asian (EAS)

AF:

0.0167

AC:

AN:

5088

South Asian (SAS)

AF:

0.00313

AC:

AN:

4790

European-Finnish (FIN)

AF:

0.0101

AC:

104

AN:

10268

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00117

AC:

AN:

67684

Other (OTH)

AF:

0.00285

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

103

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00110

Hom.:

Bravo

AF:

0.00300

ExAC

AF:

0.00223

AC:

187

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Congenital myasthenic syndrome 8 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Benign

0.18

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.92

MetaRNN

Benign

0.0087

MetaSVM

Benign

-0.58

MutationAssessor

Uncertain

2.4

PhyloP100

4.5

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.27

Sift

Benign

0.14

Sift4G

Benign

0.10

Vest4

0.25

MVP

0.83

MPC

0.87

ClinPred

0.016

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.40

Mutation Taster

=60/40

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over