rs122460157
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_001323289.2(CDKL5):c.455G>A(p.Cys152Tyr) 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. 11/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C152R) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001323289.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDKL5 | NM_001323289.2 | c.455G>A | p.Cys152Tyr | missense_variant | 7/18 | ENST00000623535.2 | |
CDKL5 | NM_001037343.2 | c.455G>A | p.Cys152Tyr | missense_variant | 8/22 | ||
CDKL5 | NM_003159.3 | c.455G>A | p.Cys152Tyr | missense_variant | 7/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDKL5 | ENST00000623535.2 | c.455G>A | p.Cys152Tyr | missense_variant | 7/18 | 1 | NM_001323289.2 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD4 exome Cov.: 25
GnomAD4 genome ? Cov.: 23
ClinVar
Submissions by phenotype
Developmental and epileptic encephalopathy, 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | NeuroMeGen, Hospital Clinico Santiago de Compostela | Jan 01, 2018 | - - |
Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 20, 2022 | This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 152 of the CDKL5 protein (p.Cys152Tyr). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CDKL5 protein function. ClinVar contains an entry for this variant (Variation ID: 495236). This missense change has been observed in individual(s) with clinical features of CDKL5-related conditions (PMID: 31780880). In at least one individual the variant was observed to be de novo. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at