8-140532112-C-G

Position:

• chr8-140532112-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_012154.5(AGO2):​c.2512G>C​(p.Asp838His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: AGO2 NM_012154.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.86

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, AGO2

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGO2	NM_012154.5	c.2512G>C	p.Asp838His	missense_variant	19/19	ENST00000220592.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGO2	ENST00000220592.10	c.2512G>C	p.Asp838His	missense_variant	19/19	1	NM_012154.5	P1
AGO2	ENST00000519980.5	c.2410G>C	p.Asp804His	missense_variant	18/18	1
AGO2	ENST00000523609.5	c.*2097G>C		3_prime_UTR_variant, NMD_transcript_variant	18/18	1
AGO2	ENST00000520628.1	n.332G>C		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 16, 2024

The c.2512G>C (p.D838H) alteration is located in exon 19 (coding exon 19) of the AGO2 gene. This alteration results from a G to C substitution at nucleotide position 2512, causing the aspartic acid (D) at amino acid position 838 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.48	T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.2	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.3	D;D
REVEL	Uncertain	0.36
Sift	Benign	0.047	D;D
Sift4G	Benign	0.10	T;T
Polyphen		0.054	B;P
Vest4		0.72
MutPred		0.19		Gain of MoRF binding (P = 0.032);.;
MVP		0.72
MPC		1.9
ClinPred		0.88	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.45
gMVP		0.83

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: chr8-141542211;