chr1-1053827-G-C

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.5726G>C(p.Ser1909Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00364 in 1,611,076 control chromosomes in the GnomAD database, including 193 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1909R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0072 ( 36 hom., cov: 33)

Exomes 𝑓: 0.0033 ( 157 hom. )

Consequence

AGRN
NM_198576.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.71

Publications

5 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=0.0057588816).

BP6

Variant 1-1053827-G-C is Benign according to our data. Variant chr1-1053827-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0564 is higher than 0.05.

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.5726G>C	p.Ser1909Thr	missense	Exon 34 of 36	NP_940978.2
AGRN	NM_001305275.2		c.5795G>C	p.Ser1932Thr	missense	Exon 37 of 39	NP_001292204.1	O00468-1
AGRN	NM_001364727.2		c.5423G>C	p.Ser1808Thr	missense	Exon 34 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.5726G>C	p.Ser1909Thr	missense	Exon 34 of 36	ENSP00000368678.2	O00468-6
AGRN	ENST00000461111.1	TSL:1	n.1842G>C		non_coding_transcript_exon	Exon 1 of 3
AGRN	ENST00000651234.1		c.5480G>C	p.Ser1827Thr	missense	Exon 36 of 38	ENSP00000499046.1	A0A494C1I6

Frequencies

GnomAD3 genomes

AF:

0.00711

AC:

1082

AN:

152280

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00215

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0590

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00961

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000411

Gnomad OTH

AF:

0.00573

GnomAD2 exomes

AF:

0.0125

AC:

3043

AN:

243286

AF XY:

0.00929

show subpopulations

Gnomad AFR exome

AF:

0.00156

Gnomad AMR exome

AF:

0.0821

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00702

Gnomad FIN exome

AF:

0.0000489

Gnomad NFE exome

AF:

0.000464

Gnomad OTH exome

AF:

0.00894

GnomAD4 exome

AF:

0.00327

AC:

4764

AN:

1458678

Hom.:

157

Cov.:

AF XY:

0.00283

AC XY:

2054

AN XY:

725460

show subpopulations

African (AFR)

AF:

0.000926

AC:

AN:

33472

American (AMR)

AF:

0.0784

AC:

3472

AN:

44310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26062

East Asian (EAS)

AF:

0.0204

AC:

810

AN:

39612

South Asian (SAS)

AF:

0.000198

AC:

AN:

85656

European-Finnish (FIN)

AF:

0.0000191

AC:

AN:

52284

Middle Eastern (MID)

AF:

0.000529

AC:

AN:

5670

European-Non Finnish (NFE)

AF:

0.000220

AC:

245

AN:

1111346

Other (OTH)

AF:

0.00307

AC:

185

AN:

60266

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

353

705

1058

1410

1763

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

186

248

310

<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:

0.00717

AC:

1093

AN:

152398

Hom.:

Cov.:

AF XY:

0.00782

AC XY:

583

AN XY:

74516

show subpopulations

African (AFR)

AF:

0.00214

AC:

AN:

41602

American (AMR)

AF:

0.0596

AC:

912

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00982

AC:

AN:

5192

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000412

AC:

AN:

68042

Other (OTH)

AF:

0.00567

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

114

172

229

286

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00248

Hom.:

Bravo

AF:

0.0112

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.000582

AC:

ExAC

AF:

0.00910

AC:

1102

Asia WGS

AF:

0.00520

AC:

AN:

3478

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

0.16

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Benign

0.50

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.87

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

MetaRNN

Benign

0.0058

MetaSVM

Benign

-0.89

PhyloP100

3.7

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.4

REVEL

Uncertain

0.32

Sift

Benign

0.58

Sift4G

Uncertain

0.036

Vest4

0.53

MPC

0.39

ClinPred

0.035

GERP RS

-0.78

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.55

Mutation Taster

=94/6

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

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