chr8-140539376-T-C

Position:

• chr8-140539376-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_012154.5(AGO2):​c.2113A>G​(p.Ile705Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: AGO2 NM_012154.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.63

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), AGO2. . Gene score misZ 6.0576 (greater than the threshold 3.09). Trascript score misZ 6.9725 (greater than threshold 3.09). GenCC has associacion of gene with Lessel-Kreienkamp syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.18496454).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGO2	NM_012154.5	c.2113A>G	p.Ile705Val	missense_variant	16/19	ENST00000220592.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGO2	ENST00000220592.10	c.2113A>G	p.Ile705Val	missense_variant	16/19	1	NM_012154.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461788 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727196

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.32	T;.
Eigen	Benign	-0.19
Eigen_PC	Benign	0.016
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.83	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.71	N;N
REVEL	Benign	0.040
Sift	Benign	0.71	T;T
Sift4G	Benign	0.63	T;T
Polyphen		0.024	B;B
Vest4		0.20
MutPred		0.58		Loss of sheet (P = 0.1501);Loss of sheet (P = 0.1501);
MVP		0.44
MPC		1.5
ClinPred		0.68	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.81

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-141549475;