8-140564095-A-G

Variant names:

• chr8-140564095-A-G
• rs2944755
• NM_012154.5:c.337-1461T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_012154.5(AGO2):​c.337-1461T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.809 in 152,232 control chromosomes in the GnomAD database, including 50,572 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 0.81 (50572 hom., cov: 34)
• Consequence: AGO2 NM_012154.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.48
• Publications: 8 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=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.967 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.337-1461T>C		intron	N/A	NP_036286.2
	AGO2	NM_001164623.3		c.337-1461T>C		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.337-1461T>C		intron	N/A	ENSP00000220592.5
	AGO2	ENST00000519980.5	TSL:1	c.337-1461T>C		intron	N/A	ENSP00000430176.1
	AGO2	ENST00000523609.5	TSL:1	n.144-1461T>C		intron	N/A	ENSP00000430164.1

Frequencies

GnomAD3 genomes AF: 0.809 AC: 123072 AN: 152114 Hom.: 50502 Cov.: 34

Gnomad AFR AF: 0.938

Gnomad AMI AF: 0.760

Gnomad AMR AF: 0.812

Gnomad ASJ AF: 0.737

Gnomad EAS AF: 0.989

Gnomad SAS AF: 0.859

Gnomad FIN AF: 0.762

Gnomad MID AF: 0.750

Gnomad NFE AF: 0.726

Gnomad OTH AF: 0.780

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

GnomAD4 genome AF: 0.809 AC: 123204 AN: 152232 Hom.: 50572 Cov.: 34 AF XY: 0.814 AC XY: 60571 AN XY: 74420

African (AFR) AF: 0.938 AC: 38976 AN: 41558

American (AMR) AF: 0.812 AC: 12431 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.737 AC: 2559 AN: 3472

East Asian (EAS) AF: 0.989 AC: 5118 AN: 5174

South Asian (SAS) AF: 0.859 AC: 4146 AN: 4828

European-Finnish (FIN) AF: 0.762 AC: 8064 AN: 10576

Middle Eastern (MID) AF: 0.765 AC: 225 AN: 294

European-Non Finnish (NFE) AF: 0.726 AC: 49343 AN: 68002

Other (OTH) AF: 0.782 AC: 1652 AN: 2112

Alfa AF: 0.760 Hom.: 102294

Bravo AF: 0.817

Asia WGS AF: 0.933 AC: 3243 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.35
DANN	Benign	0.20
PhyloP100		-1.5
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: rs2944755; hg19: chr8-141574194;