rs786204962
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_001323289.2(CDKL5):c.59G>A(p.Gly20Asp) 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: 23)
Consequence
CDKL5
NM_001323289.2 missense
NM_001323289.2 missense
Scores
11
3
3
Clinical Significance
Conservation
PhyloP100: 8.37
Genes affected
CDKL5 (HGNC:11411): (cyclin dependent kinase like 5) This gene is a member of Ser/Thr protein kinase family and encodes a phosphorylated protein with protein kinase activity. Mutations in this gene have been associated with X-linked infantile spasm syndrome (ISSX), also known as X-linked West syndrome, and Rett syndrome (RTT). Alternate transcriptional splice variants have been characterized. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.987
PP5
Variant X-18507155-G-A is Pathogenic according to our data. Variant chrX-18507155-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189548.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18507155-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CDKL5 | NM_001323289.2 | c.59G>A | p.Gly20Asp | missense_variant | Exon 2 of 18 | ENST00000623535.2 | NP_001310218.1 | |
| CDKL5 | NM_001037343.2 | c.59G>A | p.Gly20Asp | missense_variant | Exon 3 of 22 | NP_001032420.1 | ||
| CDKL5 | NM_003159.3 | c.59G>A | p.Gly20Asp | missense_variant | Exon 2 of 21 | NP_003150.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
23
GnomAD4 exome Cov.: 25
GnomAD4 exome
Cov.:
25
GnomAD4 genome
GnomAD4 genome
Cov.:
23
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
CDKL5 disorder Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | curation | Centre for Population Genomics, CPG | Jul 04, 2024 | This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria. Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as likely pathogenic. At least the following criteria are met: Occurs in the well-characterized ATP binding region of CDKL5 (PM1). Another missense variant in the same codon has been classified as pathogenic (PM5, ClinVar Variation ID: 918032). Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). This variant is absent from gnomAD (PM2_Supporting). - |
not provided Pathogenic:1
| Likely pathogenic, no assertion criteria provided | curation | RettBASE | Mar 13, 2014 | Conserved amino acid in the catalytic domain - |
Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 05, 2022 | This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 20 of the CDKL5 protein (p.Gly20Asp). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Gly20 amino acid residue in CDKL5. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20397747, 29420175). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects CDKL5 function (PMID: 30266825). 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: 189548). This variant has not been reported in the literature in individuals affected with CDKL5-related conditions. This variant is not present in population databases (gnomAD no frequency). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;T;.;T;.;.;.;.
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
.;T;T;T;D;D;T;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;.;.;M;.;.;.;M
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;.;.;D;.;.;.;.
REVEL
Pathogenic
Sift
Pathogenic
D;.;.;D;.;.;.;.
Sift4G
Uncertain
D;.;.;D;D;D;D;D
Polyphen
D;.;.;D;.;.;.;.
Vest4
MutPred
Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP
MPC
3.0
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at