chr8-140558523-G-A

Variant names:

• chr8-140558523-G-A
• rs2292778
• NM_012154.5:c.840C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_012154.5(AGO2):​c.840C>T​(p.Arg280Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.553 in 1,613,924 control chromosomes in the GnomAD database, including 251,392 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 0.62 (30639 hom., cov: 34)
  • Exomes 𝑓: 0.55 (220753 hom.)
• Consequence: AGO2 NM_012154.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.18
• Publications: 23 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP7: Synonymous conserved (PhyloP=-2.18 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.813 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGO2	NM_012154.5	MANE Select	c.840C>T	p.Arg280Arg	synonymous	Exon 7 of 19	NP_036286.2
	AGO2	NM_001164623.3		c.840C>T	p.Arg280Arg	synonymous	Exon 7 of 18	NP_001158095.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGO2	ENST00000220592.10	TSL:1 MANE Select	c.840C>T	p.Arg280Arg	synonymous	Exon 7 of 19	ENSP00000220592.5
	AGO2	ENST00000519980.5	TSL:1	c.840C>T	p.Arg280Arg	synonymous	Exon 7 of 18	ENSP00000430176.1
	AGO2	ENST00000523609.5	TSL:1	n.*425C>T		non_coding_transcript_exon	Exon 6 of 18	ENSP00000430164.1

Frequencies

GnomAD3 genomes AF: 0.621 AC: 94372 AN: 152054 Hom.: 30591 Cov.: 34

Gnomad AFR AF: 0.821

Gnomad AMI AF: 0.372

Gnomad AMR AF: 0.629

Gnomad ASJ AF: 0.550

Gnomad EAS AF: 0.619

Gnomad SAS AF: 0.617

Gnomad FIN AF: 0.494

Gnomad MID AF: 0.586

Gnomad NFE AF: 0.525

Gnomad OTH AF: 0.587

GnomAD2 exomes AF: 0.581 AC: 145947 AN: 251404 AF XY: 0.573

Gnomad AFR exome AF: 0.837

Gnomad AMR exome AF: 0.671

Gnomad ASJ exome AF: 0.544

Gnomad EAS exome AF: 0.626

Gnomad FIN exome AF: 0.491

Gnomad NFE exome AF: 0.521

Gnomad OTH exome AF: 0.547

GnomAD4 exome AF: 0.546 AC: 798161 AN: 1461752 Hom.: 220753 Cov.: 62 AF XY: 0.546 AC XY: 397044 AN XY: 727176

African (AFR) AF: 0.830 AC: 27782 AN: 33478

American (AMR) AF: 0.662 AC: 29614 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.547 AC: 14293 AN: 26134

East Asian (EAS) AF: 0.587 AC: 23312 AN: 39698

South Asian (SAS) AF: 0.618 AC: 53273 AN: 86248

European-Finnish (FIN) AF: 0.494 AC: 26379 AN: 53418

Middle Eastern (MID) AF: 0.597 AC: 3441 AN: 5768

European-Non Finnish (NFE) AF: 0.527 AC: 586379 AN: 1111906

Other (OTH) AF: 0.558 AC: 33688 AN: 60392

GnomAD4 genome AF: 0.621 AC: 94482 AN: 152172 Hom.: 30639 Cov.: 34 AF XY: 0.620 AC XY: 46115 AN XY: 74390

African (AFR) AF: 0.821 AC: 34078 AN: 41524

American (AMR) AF: 0.630 AC: 9628 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.550 AC: 1911 AN: 3472

East Asian (EAS) AF: 0.619 AC: 3199 AN: 5164

South Asian (SAS) AF: 0.617 AC: 2982 AN: 4832

European-Finnish (FIN) AF: 0.494 AC: 5225 AN: 10580

Middle Eastern (MID) AF: 0.603 AC: 176 AN: 292

European-Non Finnish (NFE) AF: 0.525 AC: 35702 AN: 67988

Other (OTH) AF: 0.588 AC: 1242 AN: 2114

Alfa AF: 0.574 Hom.: 12492

Bravo AF: 0.639

Asia WGS AF: 0.642 AC: 2231 AN: 3478

EpiCase AF: 0.523

EpiControl AF: 0.515

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.21
DANN	Benign	0.85
PhyloP100		-2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2292778; hg19: chr8-141568622;