8-140551258-C-T

Variant names:

• chr8-140551258-C-T
• rs2292780
• NM_012154.5:c.1403+45G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_012154.5(AGO2):​c.1403+45G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0614 in 1,448,854 control chromosomes in the GnomAD database, including 3,043 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.077 (572 hom., cov: 33)
  • Exomes 𝑓: 0.060 (2471 hom.)
• Consequence: AGO2 NM_012154.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0250
• Publications: 8 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGO2	NM_012154.5	c.1403+45G>A		intron_variant	Intron 11 of 18	ENST00000220592.10	NP_036286.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGO2	ENST00000220592.10	c.1403+45G>A		intron_variant	Intron 11 of 18	1	NM_012154.5	ENSP00000220592.5
AGO2	ENST00000519980.5	c.1403+45G>A		intron_variant	Intron 11 of 17	1		ENSP00000430176.1
AGO2	ENST00000523609.5	n.*988+45G>A		intron_variant	Intron 10 of 17	1		ENSP00000430164.1

Frequencies

GnomAD3 genomes AF: 0.0768 AC: 11682 AN: 152160 Hom.: 569 Cov.: 33

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.0815

Gnomad AMR AF: 0.0519

Gnomad ASJ AF: 0.0704

Gnomad EAS AF: 0.0409

Gnomad SAS AF: 0.0449

Gnomad FIN AF: 0.0419

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0586

Gnomad OTH AF: 0.0692

GnomAD2 exomes AF: 0.0595 AC: 9501 AN: 159692 AF XY: 0.0587

Gnomad AFR exome AF: 0.136

Gnomad AMR exome AF: 0.0438

Gnomad ASJ exome AF: 0.0664

Gnomad EAS exome AF: 0.0411

Gnomad FIN exome AF: 0.0381

Gnomad NFE exome AF: 0.0599

Gnomad OTH exome AF: 0.0583

GnomAD4 exome AF: 0.0596 AC: 77239 AN: 1296576 Hom.: 2471 Cov.: 29 AF XY: 0.0594 AC XY: 37668 AN XY: 634430

African (AFR) AF: 0.131 AC: 3694 AN: 28148

American (AMR) AF: 0.0458 AC: 1273 AN: 27820

Ashkenazi Jewish (ASJ) AF: 0.0713 AC: 1368 AN: 19192

East Asian (EAS) AF: 0.0514 AC: 1785 AN: 34718

South Asian (SAS) AF: 0.0490 AC: 3133 AN: 63884

European-Finnish (FIN) AF: 0.0403 AC: 1848 AN: 45812

Middle Eastern (MID) AF: 0.0740 AC: 254 AN: 3432

European-Non Finnish (NFE) AF: 0.0594 AC: 60644 AN: 1021424

Other (OTH) AF: 0.0621 AC: 3240 AN: 52146

GnomAD4 genome AF: 0.0768 AC: 11689 AN: 152278 Hom.: 572 Cov.: 33 AF XY: 0.0746 AC XY: 5557 AN XY: 74462

African (AFR) AF: 0.134 AC: 5553 AN: 41562

American (AMR) AF: 0.0518 AC: 793 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0704 AC: 244 AN: 3468

East Asian (EAS) AF: 0.0410 AC: 211 AN: 5148

South Asian (SAS) AF: 0.0449 AC: 217 AN: 4828

European-Finnish (FIN) AF: 0.0419 AC: 445 AN: 10618

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0586 AC: 3987 AN: 68030

Other (OTH) AF: 0.0685 AC: 145 AN: 2116

Alfa AF: 0.0617 Hom.: 557

Bravo AF: 0.0810

Asia WGS AF: 0.0530 AC: 182 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.9
DANN	Benign	0.78
PhyloP100		0.025
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2292780; hg19: chr8-141561357; COSMIC: COSV55044928; COSMIC: COSV55044928;