8-140541225-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_012154.5(AGO2):​c.1973G>A​(p.Arg658His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000311 in 1,606,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

AGO2
NM_012154.5 missense

Scores

2
4
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.89
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 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.
BP4
Computational evidence support a benign effect (MetaRNN=0.2929688).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
AGO2NM_012154.5 linkuse as main transcriptc.1973G>A p.Arg658His missense_variant 15/19 ENST00000220592.10 NP_036286.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
AGO2ENST00000220592.10 linkuse as main transcriptc.1973G>A p.Arg658His missense_variant 15/191 NM_012154.5 ENSP00000220592 P1Q9UKV8-1
AGO2ENST00000519980.5 linkuse as main transcriptc.1973G>A p.Arg658His missense_variant 15/181 ENSP00000430176 Q9UKV8-2
AGO2ENST00000523609.5 linkuse as main transcriptc.*1558G>A 3_prime_UTR_variant, NMD_transcript_variant 14/181 ENSP00000430164
AGO2ENST00000520412.1 linkuse as main transcriptn.233G>A non_coding_transcript_exon_variant 1/42

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152212
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000275
AC:
4
AN:
1453850
Hom.:
0
Cov.:
30
AF XY:
0.00000277
AC XY:
2
AN XY:
722466
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000271
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152212
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74370
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000329
Hom.:
0
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxMay 17, 2023Not 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 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.20
BayesDel_addAF
Benign
-0.072
T
BayesDel_noAF
Benign
-0.34
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.51
D;.
Eigen
Benign
0.025
Eigen_PC
Benign
0.20
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Benign
0.014
T
MetaRNN
Benign
0.29
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.4
L;L
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.83
D
PROVEAN
Uncertain
-4.2
D;D
REVEL
Benign
0.15
Sift
Benign
0.12
T;T
Sift4G
Benign
0.22
T;T
Polyphen
0.10
B;B
Vest4
0.58
MutPred
0.42
Loss of MoRF binding (P = 0.0208);Loss of MoRF binding (P = 0.0208);
MVP
0.50
MPC
2.1
ClinPred
0.99
D
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.56
gMVP
0.86

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.

Other links and lift over

dbSNP: rs1442254850; hg19: chr8-141551324; API