chrX-18584301-TAC-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The ENST00000623535.2(CDKL5):​c.506_507del​(p.Thr169ArgfsTer36) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 22)

Consequence

CDKL5
ENST00000623535.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 9.32
Variant links:
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 18 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-18584301-TAC-T is Pathogenic according to our data. Variant chrX-18584301-TAC-T is described in ClinVar as [Pathogenic]. Clinvar id is 189592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CDKL5NM_001323289.2 linkuse as main transcriptc.506_507del p.Thr169ArgfsTer36 frameshift_variant 8/18 ENST00000623535.2 NP_001310218.1
CDKL5NM_001037343.2 linkuse as main transcriptc.506_507del p.Thr169ArgfsTer36 frameshift_variant 9/22 NP_001032420.1
CDKL5NM_003159.3 linkuse as main transcriptc.506_507del p.Thr169ArgfsTer36 frameshift_variant 8/21 NP_003150.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CDKL5ENST00000623535.2 linkuse as main transcriptc.506_507del p.Thr169ArgfsTer36 frameshift_variant 8/181 NM_001323289.2 ENSP00000485244 P1O76039-2

Frequencies

GnomAD3 genomes
Cov.:
22
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
Cov.:
22

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 2 Pathogenic:1
Pathogenic, no assertion criteria providedcurationRettBASEMar 13, 2014- -
CDKL5 disorder Pathogenic:1
Pathogenic, criteria provided, single submittercurationCentre for Population Genomics, CPGSep 18, 2024This 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 pathogenic. At least the following criteria are met: Predicted to result in loss of function, and LOF is a known mechanism of disease (PVS1). This variant is absent from gnomAD v4 (PM2_Supporting). Has been observed in at least 2 individuals with phenotypes consistent with CDKL5 disorder (PS4_Supporting). PMID: 23064044 PMID: 22872100 Variation ID: 189592 -
CDKL5-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJul 11, 2023The CDKL5 c.506_507delCA variant is predicted to result in a frameshift and premature protein termination (p.Thr169Argfs*36). To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating it is rare. Frameshift variants in CDKL5 are expected to be pathogenic, and a similar variant (c.503_504del p.Y168YfsX204) was reported to be de novo in an individual with developmental and epileptic encephalopathy (Raymond et al 2013. PubMed ID: 23064044). The c.506_507delCA (p.Thr169Argfs*36) variant is interpreted as pathogenic. -
Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 30, 2022For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 189592). This variant is also known as c.503_504del. This premature translational stop signal has been observed in individual(s) with clinical features of epileptic encephalopathy (PMID: 23064044). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Thr169Argfs*36) 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). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs786204987; hg19: chrX-18602421; API