8-140535487-C-T

Variant names:

• chr8-140535487-C-T
• rs2072680461
• NM_012154.5:c.2252G>A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_012154.5(AGO2):​c.2252G>A​(p.Cys751Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: AGO2 NM_012154.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.79

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 Pathogenic. Variant got 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the AGO2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 12 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 6.0576 (above the threshold of 3.09). Trascript score misZ: 6.9725 (above the threshold of 3.09). GenCC associations: The gene is linked to Lessel-Kreienkamp syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965
• PP5: Variant 8-140535487-C-T is Pathogenic according to our data. Variant chr8-140535487-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 995794.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-140535487-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGO2	NM_012154.5	c.2252G>A	p.Cys751Tyr	missense_variant	Exon 17 of 19	ENST00000220592.10	NP_036286.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGO2	ENST00000220592.10	c.2252G>A	p.Cys751Tyr	missense_variant	Exon 17 of 19	1	NM_012154.5	ENSP00000220592.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Oct 19, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2252G>A (p.C751Y) alteration is located in exon 17 (coding exon 17) of the AGO2 gene. This alteration results from a G to A substitution at nucleotide position 2252, causing the cysteine (C) at amino acid position 751 to be replaced by a tyrosine (Y). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported de novo in monozygotic twins and another unrelated patient with neurodevelopmental disorders, including varying degrees of intellectual disability, delayed motor development, impaired speech and receptive language development, and other variable features (Lessel, 2020). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). The p.C751 amino acid is located at the base of a loop in the PIWI domain that binds to the minor groove in the guide/target duplex and regulates the interaction between RNA and the MID domain. Functional studies showed that this alteration significantly reduces shRNA-mediated silencing of Shank3 but not δ-catenin, suggesting target mRNA specific effects of the alteration (Lessel, 2020). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

Lessel-Kreienkamp syndrome Pathogenic:1

Jan 20, 2021

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Mar 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.044	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.7	M
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-10	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.88		Gain of phosphorylation at C751 (P = 0.0668);
MVP		0.81
MPC		4.3
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.99

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

LitVar

Other links and lift over

dbSNP: rs2072680461; hg19: chr8-141545586;