X-18581890-G-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Moderate
The NM_001323289.2(CDKL5):c.404-1G>T variant causes a splice acceptor 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 23)
Consequence
CDKL5
NM_001323289.2 splice_acceptor
NM_001323289.2 splice_acceptor
Scores
3
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 10.0
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 10 ACMG points.
PVS1
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.020464793 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant X-18581890-G-T is Pathogenic according to our data. Variant chrX-18581890-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 156087.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-18581890-G-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDKL5 | NM_001323289.2 | c.404-1G>T | splice_acceptor_variant | ENST00000623535.2 | |||
CDKL5 | NM_001037343.2 | c.404-1G>T | splice_acceptor_variant | ||||
CDKL5 | NM_003159.3 | c.404-1G>T | splice_acceptor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDKL5 | ENST00000623535.2 | c.404-1G>T | splice_acceptor_variant | 1 | NM_001323289.2 | P1 |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD3 genomes
Cov.:
23
GnomAD4 exome Cov.: 24
GnomAD4 exome
Cov.:
24
GnomAD4 genome Cov.: 23
GnomAD4 genome
Cov.:
23
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Developmental and epileptic encephalopathy, 2 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2006 | - - |
Pathogenic, no assertion criteria provided | curation | RettBASE | Mar 13, 2014 | Predicted to cause exon 7 skipping - |
not provided Pathogenic:1Other:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 02, 2020 | Canonical splice site variant predicted to result in an in-frame deletion of a critical region; Deletions involving coding exons in this gene are frequently reported as pathogenic, regardless of frame prediction (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27081548, 23064044, 22670135, 19793311, 16611748, 25525159) - |
not provided, flagged submission | literature only | RettBASE | - | - - |
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
D;D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at