rs1060501860
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001323289.2(CDKL5):c.2022del(p.Phe675SerfsTer109) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. S674S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 22)
Consequence
CDKL5
NM_001323289.2 frameshift
NM_001323289.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.52
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 12 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant X-18608886-TC-T is Pathogenic according to our data. Variant chrX-18608886-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 408123.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDKL5 | NM_001323289.2 | c.2022del | p.Phe675SerfsTer109 | frameshift_variant | 13/18 | ENST00000623535.2 | |
CDKL5 | NM_001037343.2 | c.2022del | p.Phe675SerfsTer109 | frameshift_variant | 14/22 | ||
CDKL5 | NM_003159.3 | c.2022del | p.Phe675SerfsTer109 | frameshift_variant | 13/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDKL5 | ENST00000623535.2 | c.2022del | p.Phe675SerfsTer109 | frameshift_variant | 13/18 | 1 | NM_001323289.2 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD3 genomes
?
Cov.:
22
GnomAD4 exome Cov.: 27
GnomAD4 exome
Cov.:
27
GnomAD4 genome ? Cov.: 22
GnomAD4 genome
?
Cov.:
22
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 10, 2016 | For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, loss-of-function variants in CDKL5 are known to be pathogenic (PMID: 21160487,  21770923). This sequence change deletes 1 nucleotide from exon 13 of the CDKL5 mRNA (c.2022delC), causing a frameshift at codon 675. This creates a premature translational stop signal (p.Phe675Serfs*109) and is expected to result in an absent or disrupted protein product. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
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