8-140551294-G-C

Variant names:

• chr8-140551294-G-C
• rs2292779
• NM_012154.5:c.1403+9C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_012154.5(AGO2):​c.1403+9C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.553 in 1,513,356 control chromosomes in the GnomAD database, including 237,217 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (32111 hom., cov: 33)
  • Exomes 𝑓: 0.54 (205106 hom.)
• Consequence: AGO2 NM_012154.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.78
• Publications: 20 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 8-140551294-G-C is Benign according to our data. Variant chr8-140551294-G-C is described in ClinVar as Benign. ClinVar VariationId is 768267.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.854 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGO2	NM_012154.5	MANE Select	c.1403+9C>G		intron	N/A	NP_036286.2
	AGO2	NM_001164623.3		c.1403+9C>G		intron	N/A	NP_001158095.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGO2	ENST00000220592.10	TSL:1 MANE Select	c.1403+9C>G		intron	N/A	ENSP00000220592.5
	AGO2	ENST00000519980.5	TSL:1	c.1403+9C>G		intron	N/A	ENSP00000430176.1
	AGO2	ENST00000523609.5	TSL:1	n.*988+9C>G		intron	N/A	ENSP00000430164.1

Frequencies

GnomAD3 genomes AF: 0.632 AC: 96113 AN: 151980 Hom.: 32056 Cov.: 33

Gnomad AFR AF: 0.862

Gnomad AMI AF: 0.375

Gnomad AMR AF: 0.632

Gnomad ASJ AF: 0.548

Gnomad EAS AF: 0.623

Gnomad SAS AF: 0.620

Gnomad FIN AF: 0.494

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.525

Gnomad OTH AF: 0.595

GnomAD2 exomes AF: 0.574 AC: 117904 AN: 205340 AF XY: 0.565

Gnomad AFR exome AF: 0.875

Gnomad AMR exome AF: 0.667

Gnomad ASJ exome AF: 0.526

Gnomad EAS exome AF: 0.627

Gnomad FIN exome AF: 0.485

Gnomad NFE exome AF: 0.514

Gnomad OTH exome AF: 0.539

GnomAD4 exome AF: 0.545 AC: 741325 AN: 1361258 Hom.: 205106 Cov.: 54 AF XY: 0.544 AC XY: 365284 AN XY: 671184

African (AFR) AF: 0.871 AC: 26372 AN: 30292

American (AMR) AF: 0.656 AC: 23993 AN: 36552

Ashkenazi Jewish (ASJ) AF: 0.538 AC: 12141 AN: 22568

East Asian (EAS) AF: 0.585 AC: 21192 AN: 36214

South Asian (SAS) AF: 0.616 AC: 46092 AN: 74872

European-Finnish (FIN) AF: 0.491 AC: 24527 AN: 49966

Middle Eastern (MID) AF: 0.576 AC: 2165 AN: 3756

European-Non Finnish (NFE) AF: 0.527 AC: 554023 AN: 1052006

Other (OTH) AF: 0.560 AC: 30820 AN: 55032

GnomAD4 genome AF: 0.633 AC: 96230 AN: 152098 Hom.: 32111 Cov.: 33 AF XY: 0.631 AC XY: 46944 AN XY: 74342

African (AFR) AF: 0.861 AC: 35785 AN: 41542

American (AMR) AF: 0.633 AC: 9678 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.548 AC: 1903 AN: 3472

East Asian (EAS) AF: 0.623 AC: 3199 AN: 5136

South Asian (SAS) AF: 0.620 AC: 2983 AN: 4812

European-Finnish (FIN) AF: 0.494 AC: 5213 AN: 10560

Middle Eastern (MID) AF: 0.605 AC: 178 AN: 294

European-Non Finnish (NFE) AF: 0.525 AC: 35695 AN: 67968

Other (OTH) AF: 0.594 AC: 1254 AN: 2110

Alfa AF: 0.463 Hom.: 2257

Bravo AF: 0.652

Asia WGS AF: 0.652 AC: 2265 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Aug 12, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

AGO2-related disorder Benign:1

Mar 04, 2022

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.024
DANN	Benign	0.49
PhyloP100		-3.8
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)		0.020		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: rs2292779; hg19: chr8-141561393; COSMIC: COSV55044939; COSMIC: COSV55044939;