NM_012154.5:c.518+54C>A

Variant names:

• chr8-140562399-G-T
• rs2292773
• NM_012154.5:c.518+54C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_012154.5(AGO2):​c.518+54C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000711 in 1,405,856 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: AGO2 NM_012154.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.99
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGO2	NM_012154.5	c.518+54C>A		intron_variant	Intron 4 of 18	ENST00000220592.10	NP_036286.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGO2	ENST00000220592.10	c.518+54C>A		intron_variant	Intron 4 of 18	1	NM_012154.5	ENSP00000220592.5
AGO2	ENST00000519980.5	c.518+54C>A		intron_variant	Intron 4 of 17	1		ENSP00000430176.1
AGO2	ENST00000523609.5	n.*103+54C>A		intron_variant	Intron 3 of 17	1		ENSP00000430164.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.11e-7 AC: 1 AN: 1405856 Hom.: 0 AF XY: 0.00000144 AC XY: 1 AN XY: 692906

African (AFR) AF: 0.00 AC: 0 AN: 32224

American (AMR) AF: 0.00 AC: 0 AN: 40034

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23632

East Asian (EAS) AF: 0.00 AC: 0 AN: 38830

South Asian (SAS) AF: 0.00 AC: 0 AN: 81444

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46712

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3956

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1081160

Other (OTH) AF: 0.0000173 AC: 1 AN: 57864

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.17
DANN	Benign	0.65
PhyloP100		-2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs2292773; hg19: chr8-141572498;