dbSNP rs1015396973: AGRN:p.Arg1395Ser (chr1-1048944-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001305275.2(AGRN):c.4183C>A(p.Arg1395Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1395C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 26)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

AGRN
NM_001305275.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.96

Publications

1 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.825

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001305275.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AGRN	NM_198576.4	MANE Select	c.4183C>A	p.Arg1395Ser	missense	Exon 24 of 36	NP_940978.2
AGRN	NM_001305275.2		c.4183C>A	p.Arg1395Ser	missense	Exon 24 of 39	NP_001292204.1
AGRN	NM_001364727.2		c.3868C>A	p.Arg1290Ser	missense	Exon 23 of 36	NP_001351656.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AGRN	ENST00000379370.7	TSL:1 MANE Select	c.4183C>A	p.Arg1395Ser	missense	Exon 24 of 36	ENSP00000368678.2
AGRN	ENST00000651234.1		c.3868C>A	p.Arg1290Ser	missense	Exon 23 of 38	ENSP00000499046.1
AGRN	ENST00000652369.2		c.3868C>A	p.Arg1290Ser	missense	Exon 23 of 35	ENSP00000498543.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1414916

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

699574

African (AFR)

AF:

0.00

AC:

AN:

32420

American (AMR)

AF:

0.00

AC:

AN:

38730

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25330

East Asian (EAS)

AF:

0.00

AC:

AN:

37278

South Asian (SAS)

AF:

0.00

AC:

AN:

80412

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48660

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4192

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1089448

Other (OTH)

AF:

0.00

AC:

AN:

58446

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Uncertain

0.051

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

(source)

DANN

Uncertain

0.99

Eigen

Benign

0.18

Eigen_PC

Benign

0.16

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.83

MetaSVM

Benign

-0.44

MutationAssessor

Benign

1.4

PhyloP100

3.0

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-2.1

REVEL

Uncertain

0.42

Sift

Benign

0.23

Sift4G

Pathogenic

0.0

Vest4

0.74

MutPred

0.51

Loss of phosphorylation at T1393 (P = 0.1009)

MVP

0.84

MPC

0.41

ClinPred

0.91

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.78

Mutation Taster

=40/60

disease causing

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over