8-140535487-C-T
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PP2PP3_StrongPP5_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
Consequence
NM_012154.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
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
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Inborn genetic diseases Pathogenic:1
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
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not provided Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at