rs786204973
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001323289.2(CDKL5):c.-162-2A>G variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 23)
Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )
Failed GnomAD Quality Control
Consequence
CDKL5
NM_001323289.2 splice_acceptor, intron
NM_001323289.2 splice_acceptor, intron
Scores
2
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 4.78
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
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.3, offset of -26, new splice context is: tgcaaatataaaacttacAGctt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant X-18506933-A-G is Pathogenic according to our data. Variant chrX-18506933-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189565.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 |
---|---|---|---|---|---|---|---|---|
CDKL5 | NM_001323289.2 | c.-162-2A>G | splice_acceptor_variant, intron_variant | ENST00000623535.2 | NP_001310218.1 | |||
CDKL5 | NM_001037343.2 | c.-162-2A>G | splice_acceptor_variant, intron_variant | NP_001032420.1 | ||||
CDKL5 | NM_003159.3 | c.-162-2A>G | splice_acceptor_variant, intron_variant | NP_003150.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CDKL5 | ENST00000623535.2 | c.-162-2A>G | splice_acceptor_variant, intron_variant | 1 | NM_001323289.2 | ENSP00000485244.1 |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD3 genomes
Cov.:
23
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 328559Hom.: 0 Cov.: 3 AF XY: 0.00 AC XY: 0AN XY: 105131
GnomAD4 exome
Data not reliable, filtered out with message: AC0
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328559
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3
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AN XY:
105131
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GnomAD4 genome Cov.: 23
GnomAD4 genome
Cov.:
23
ClinVar
Significance: Pathogenic/Likely 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, no assertion criteria provided | curation | RettBASE | Mar 13, 2014 | Splice site mutation causing skipping of exon 2 (loss of AUG codon) - |
CDKL5 disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | curation | Centre for Population Genomics, CPG | Sep 20, 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: This variant has been identified as a de novo occurrence in an individual with CDKL5 disorder without confirmation of paternity and maternity (PM6, PMID: 19793311). Well-established in vitro or in vivo functional studies strongly supportive of a damaging effect on the protein function (PS3). This variant is absent from gnomAD (PM2_Supporting). - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 08, 2021 | Observed in hemizygous state in a patient with seizures in the literature (Dimassi et al., 2015); Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts; however, limited data are available (Lek et al., 2016); This variant is associated with the following publications: (PMID: 29264392, 25525159, 22670135, 22779007, 27054081, 19793311) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
Find out detailed SpliceAI scores and Pangolin per-transcript scores at