NM_012154.5:c.2271+1091C>A

Variant names:

• chr8-140534377-G-T
• rs6994531
• NM_012154.5:c.2271+1091C>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.2271+1091C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0394 in 152,324 control chromosomes in the GnomAD database, including 156 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 0.039 (156 hom., cov: 34)
• Consequence: AGO2 NM_012154.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0450
• Publications: 1 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0706 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGO2	NM_012154.5	c.2271+1091C>A		intron_variant	Intron 17 of 18	ENST00000220592.10	NP_036286.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGO2	ENST00000220592.10	c.2271+1091C>A		intron_variant	Intron 17 of 18	1	NM_012154.5	ENSP00000220592.5
AGO2	ENST00000519980.5	c.2170-1762C>A		intron_variant	Intron 16 of 17	1		ENSP00000430176.1
AGO2	ENST00000523609.5	n.*1856+1091C>A		intron_variant	Intron 16 of 17	1		ENSP00000430164.1
AGO2	ENST00000520412.1	n.531+1091C>A		intron_variant	Intron 3 of 3	2

Frequencies

GnomAD3 genomes AF: 0.0394 AC: 5994 AN: 152206 Hom.: 156 Cov.: 34

Gnomad AFR AF: 0.0729

Gnomad AMI AF: 0.0363

Gnomad AMR AF: 0.0225

Gnomad ASJ AF: 0.0308

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0507

Gnomad FIN AF: 0.0102

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0297

Gnomad OTH AF: 0.0482

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

GnomAD4 genome AF: 0.0394 AC: 5999 AN: 152324 Hom.: 156 Cov.: 34 AF XY: 0.0379 AC XY: 2820 AN XY: 74478

African (AFR) AF: 0.0728 AC: 3025 AN: 41568

American (AMR) AF: 0.0225 AC: 344 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0308 AC: 107 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.0507 AC: 245 AN: 4828

European-Finnish (FIN) AF: 0.0102 AC: 108 AN: 10624

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0297 AC: 2019 AN: 68030

Other (OTH) AF: 0.0477 AC: 101 AN: 2116

Alfa AF: 0.0455 Hom.: 64

Bravo AF: 0.0407

Asia WGS AF: 0.0240 AC: 86 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.6
DANN	Benign	0.69
PhyloP100		-0.045
Mutation Taster		=100/0	polymorphism

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: rs6994531; hg19: chr8-141544476;