8-140567423-C-T

Variant names:

• chr8-140567423-C-T
• rs3735805
• NM_012154.5:c.337-4789G>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.337-4789G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 152,276 control chromosomes in the GnomAD database, including 1,349 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 0.12 (1349 hom., cov: 32)
• Consequence: AGO2 NM_012154.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.761
• Publications: 4 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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.32 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGO2	NM_012154.5	c.337-4789G>A		intron_variant	Intron 3 of 18	ENST00000220592.10	NP_036286.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGO2	ENST00000220592.10	c.337-4789G>A		intron_variant	Intron 3 of 18	1	NM_012154.5	ENSP00000220592.5
AGO2	ENST00000519980.5	c.337-4789G>A		intron_variant	Intron 3 of 17	1		ENSP00000430176.1
AGO2	ENST00000523609.5	n.144-4789G>A		intron_variant	Intron 2 of 17	1		ENSP00000430164.1

Frequencies

GnomAD3 genomes AF: 0.121 AC: 18423 AN: 152158 Hom.: 1343 Cov.: 32

Gnomad AFR AF: 0.0694

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.0662

Gnomad EAS AF: 0.332

Gnomad SAS AF: 0.182

Gnomad FIN AF: 0.179

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.129

Gnomad OTH AF: 0.109

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.121 AC: 18439 AN: 152276 Hom.: 1349 Cov.: 32 AF XY: 0.125 AC XY: 9280 AN XY: 74460

African (AFR) AF: 0.0694 AC: 2883 AN: 41554

American (AMR) AF: 0.116 AC: 1769 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0662 AC: 230 AN: 3472

East Asian (EAS) AF: 0.333 AC: 1723 AN: 5170

South Asian (SAS) AF: 0.183 AC: 881 AN: 4822

European-Finnish (FIN) AF: 0.179 AC: 1901 AN: 10606

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.129 AC: 8781 AN: 68024

Other (OTH) AF: 0.107 AC: 226 AN: 2116

Alfa AF: 0.127 Hom.: 1398

Bravo AF: 0.117

Asia WGS AF: 0.246 AC: 854 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.0
DANN	Benign	0.51
PhyloP100		-0.76
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: rs3735805; hg19: chr8-141577522;