Genetic Variant NM_012154.5:c.2452G>A (chr8-140532435-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP2

The NM_012154.5(AGO2):c.2452G>A(p.Val818Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

AGO2
NM_012154.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.86

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

Lessel-Kreienkamp syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Illumina, Labcorp Genetics (formerly Invitae), ClinGen

AGO2 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;

PP2

Missense variant in the AGO2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 12 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 6.0576 (above the threshold of 3.09). Trascript score misZ: 6.9725 (above the threshold of 3.09). GenCC associations: The gene is linked to Lessel-Kreienkamp syndrome.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012154.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGO2	NM_012154.5	MANE Select	c.2452G>A	p.Val818Met	missense	Exon 18 of 19	NP_036286.2
	AGO2	NM_001164623.3		c.2350G>A	p.Val784Met	missense	Exon 17 of 18	NP_001158095.1	Q9UKV8-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AGO2	ENST00000220592.10	TSL:1 MANE Select	c.2452G>A	p.Val818Met	missense	Exon 18 of 19	ENSP00000220592.5	Q9UKV8-1
AGO2	ENST00000519980.5	TSL:1	c.2350G>A	p.Val784Met	missense	Exon 17 of 18	ENSP00000430176.1	Q9UKV8-2
AGO2	ENST00000523609.5	TSL:1	n.*2037G>A		non_coding_transcript_exon	Exon 17 of 18	ENSP00000430164.1	E5RGG9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Benign

-0.074

BayesDel_noAF

Benign

-0.34

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.48

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

M_CAP

Benign

0.033

MetaRNN

Uncertain

0.64

MetaSVM

Benign

-1.2

MutationAssessor

Benign

1.7

PhyloP100

7.9

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-2.3

REVEL

Benign

0.24

Sift

Benign

0.065

Sift4G

Benign

0.23

Polyphen

0.43

Vest4

0.65

MutPred

0.50

Gain of catalytic residue at V818 (P = 0.0547)

MVP

0.60

MPC

2.4

ClinPred

0.89

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.39

gMVP

0.83

Mutation Taster

=26/74

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

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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