rs587783158
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_001323289.2(CDKL5):c.2596C>T(p.Gln866Ter) variant causes a stop gained change. 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 Pathogenic (★★).
Frequency
Genomes: not found (cov: 22)
Consequence
CDKL5
NM_001323289.2 stop_gained
NM_001323289.2 stop_gained
Scores
3
1
1
Clinical Significance
Conservation
PhyloP100: 4.19
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.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 14 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant X-18628470-C-T is Pathogenic according to our data. Variant chrX-18628470-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 156691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDKL5 | NM_001323289.2 | c.2596C>T | p.Gln866Ter | stop_gained | 18/18 | ENST00000623535.2 | |
CDKL5 | NM_001037343.2 | c.2596C>T | p.Gln866Ter | stop_gained | 19/22 | ||
CDKL5 | NM_003159.3 | c.2596C>T | p.Gln866Ter | stop_gained | 18/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDKL5 | ENST00000623535.2 | c.2596C>T | p.Gln866Ter | stop_gained | 18/18 | 1 | NM_001323289.2 | P1 | |
CDKL5 | ENST00000379989.6 | c.2596C>T | p.Gln866Ter | stop_gained | 19/22 | 1 | |||
CDKL5 | ENST00000379996.7 | c.2596C>T | p.Gln866Ter | stop_gained | 18/21 | 1 | |||
CDKL5 | ENST00000674046.1 | c.2719C>T | p.Gln907Ter | stop_gained | 19/19 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD3 genomes
?
Cov.:
22
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 22
GnomAD4 genome
?
Cov.:
22
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Developmental and epileptic encephalopathy, 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Nov 16, 2012 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 12, 2012 | The Gln866Stop nonsense mutation in the CDKL5 gene is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant is found in EPILEPSY panel(s). - |
Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 31, 2022 | This sequence change creates a premature translational stop signal (p.Gln866*) in the CDKL5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CDKL5 are known to be pathogenic (PMID: 22872100). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 156691). This premature translational stop signal has been observed in individual(s) with CDKL5-related conditions (PMID: 29655203). This variant is not present in population databases (gnomAD no frequency). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A
Vest4
GERP RS
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