8-140524099-A-G

Variant names:

• chr8-140524099-A-G
• rs2977451
• NM_012154.5:c.*7945T>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.*7945T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.828 in 152,206 control chromosomes in the GnomAD database, including 52,355 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 0.83 (52328 hom., cov: 31)
  • Exomes 𝑓: 0.83 (27 hom.)
• Consequence: AGO2 NM_012154.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.818
• Publications: 10 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=-0.73).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.973 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.*7945T>C		3_prime_UTR	Exon 19 of 19	NP_036286.2
	AGO2	NM_001164623.3		c.*7945T>C		3_prime_UTR	Exon 18 of 18	NP_001158095.1	Q9UKV8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGO2	ENST00000220592.10	TSL:1 MANE Select	c.*7945T>C		3_prime_UTR	Exon 19 of 19	ENSP00000220592.5	Q9UKV8-1

Frequencies

GnomAD3 genomes AF: 0.828 AC: 125903 AN: 152010 Hom.: 52301 Cov.: 31

Gnomad AFR AF: 0.764

Gnomad AMI AF: 0.770

Gnomad AMR AF: 0.860

Gnomad ASJ AF: 0.825

Gnomad EAS AF: 0.996

Gnomad SAS AF: 0.889

Gnomad FIN AF: 0.851

Gnomad MID AF: 0.807

Gnomad NFE AF: 0.840

Gnomad OTH AF: 0.832

GnomAD4 exome AF: 0.833 AC: 65 AN: 78 Hom.: 27 Cov.: 0 AF XY: 0.880 AC XY: 44 AN XY: 50

African (AFR) AF: 0.750 AC: 3 AN: 4

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 2 AN: 2

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.667 AC: 4 AN: 6

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.855 AC: 53 AN: 62

Other (OTH) AF: 0.750 AC: 3 AN: 4

GnomAD4 genome AF: 0.828 AC: 125981 AN: 152128 Hom.: 52328 Cov.: 31 AF XY: 0.831 AC XY: 61788 AN XY: 74362

African (AFR) AF: 0.764 AC: 31677 AN: 41470

American (AMR) AF: 0.860 AC: 13141 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.825 AC: 2862 AN: 3470

East Asian (EAS) AF: 0.996 AC: 5165 AN: 5186

South Asian (SAS) AF: 0.888 AC: 4284 AN: 4824

European-Finnish (FIN) AF: 0.851 AC: 9010 AN: 10588

Middle Eastern (MID) AF: 0.823 AC: 242 AN: 294

European-Non Finnish (NFE) AF: 0.840 AC: 57142 AN: 67996

Other (OTH) AF: 0.833 AC: 1757 AN: 2108

Alfa AF: 0.838 Hom.: 97129

Bravo AF: 0.826

Asia WGS AF: 0.930 AC: 3232 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	7.0
DANN	Benign	0.86
PhyloP100		0.82

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: rs2977451; hg19: chr8-141534198;