Variant 8-140539349-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PP2PP3_StrongPP5_Very_Strong

The NM_012154.5(AGO2):c.2140C>T(p.Arg714Trp) 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. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Consequence

AGO2
NM_012154.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 1.62

Variant links:

Genes affected

AGO2 (HGNC:3263): (argonaute RISC catalytic component 2) This gene encodes a member of the Argonaute family of proteins which play a role in RNA interference. The encoded protein is highly basic, and contains a PAZ domain and a PIWI domain. It may interact with dicer1 and play a role in short-interfering-RNA-mediated gene silencing. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

AGO2 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), AGO2. . Gene score misZ 6.0576 (greater than the threshold 3.09). Trascript score misZ 6.9725 (greater than threshold 3.09). GenCC has associacion of gene with Lessel-Kreienkamp syndrome.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.986

PP5

Variant 8-140539349-G-A is Pathogenic according to our data. Variant chr8-140539349-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1316034.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGO2	NM_012154.5 linkuse as main transcript	c.2140C>T	p.Arg714Trp	missense_variant	16/19	ENST00000220592.10	NP_036286.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGO2	ENST00000220592.10 linkuse as main transcript	c.2140C>T	p.Arg714Trp	missense_variant	16/19	1	NM_012154.5	ENSP00000220592	P1	Q9UKV8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics laboratory, Necker Hospital	Apr 20, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 22, 2024	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Neurodevelopmental disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Nov 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.17

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

D;.

Eigen

Uncertain

0.27

Eigen_PC

Benign

0.0096

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.97

D;D

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Uncertain

0.27

MutationAssessor

Pathogenic

4.5

H;H

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-7.4

D;D

REVEL

Pathogenic

0.68

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.92

MutPred

0.96

Loss of disorder (P = 0.0748);Loss of disorder (P = 0.0748);

MVP

0.92

MPC

3.0

ClinPred

1.0

GERP RS

0.060

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.96

gMVP

0.99

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over