rs267608429
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The ENST00000623535.2(CDKL5):āc.125A>Gā(p.Lys42Arg) variant causes a missense 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 Likely pathogenic (ā ā ).
Frequency
Genomes: not found (cov: 21)
Exomes š: 0.0 ( 0 hom. 0 hem. )
Failed GnomAD Quality Control
Consequence
CDKL5
ENST00000623535.2 missense
ENST00000623535.2 missense
Scores
11
4
2
Clinical Significance
Conservation
PhyloP100: 4.01
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.
PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in ENST00000623535.2
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.905
PP5
Variant X-18564502-A-G is Pathogenic according to our data. Variant chrX-18564502-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 143772.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.125A>G | p.Lys42Arg | missense_variant | 4/18 | ENST00000623535.2 | NP_001310218.1 | |
CDKL5 | NM_001037343.2 | c.125A>G | p.Lys42Arg | missense_variant | 5/22 | NP_001032420.1 | ||
CDKL5 | NM_003159.3 | c.125A>G | p.Lys42Arg | missense_variant | 4/21 | NP_003150.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CDKL5 | ENST00000623535.2 | c.125A>G | p.Lys42Arg | missense_variant | 4/18 | 1 | NM_001323289.2 | ENSP00000485244 | P1 |
Frequencies
GnomAD3 genomes Cov.: 21
GnomAD3 genomes
Cov.:
21
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 987881Hom.: 0 Cov.: 18 AF XY: 0.00 AC XY: 0AN XY: 279289
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
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0
AN:
987881
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Cov.:
18
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AC XY:
0
AN XY:
279289
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 21
GnomAD4 genome
Cov.:
21
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, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
CDKL5 disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | curation | Centre for Population Genomics, CPG | Jul 11, 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 is absent from gnomAD v4 (PM2_Supporting). Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). Occurs in the well-characterized ATP binding region of CDKL5 (PM1). Well-established in vitro or in vivo functional studies supportive of a damaging effect on the protein function (PS3). PMID: 29474534, PMID:20861382 , PMID:16935860 - |
not provided Pathogenic:1
Pathogenic, no assertion criteria provided | research | RettBASE | Feb 15, 2011 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;T;.;T;.;.;.;.
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
.;D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;.;.;M;.;.;.;M
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;.;.;D;.;.;.;.
REVEL
Pathogenic
Sift
Uncertain
D;.;.;D;.;.;.;.
Sift4G
Pathogenic
D;.;.;D;D;D;D;D
Polyphen
D;.;.;D;.;.;.;.
Vest4
MutPred
Loss of methylation at K42 (P = 8e-04);Loss of methylation at K42 (P = 8e-04);Loss of methylation at K42 (P = 8e-04);Loss of methylation at K42 (P = 8e-04);Loss of methylation at K42 (P = 8e-04);Loss of methylation at K42 (P = 8e-04);Loss of methylation at K42 (P = 8e-04);Loss of methylation at K42 (P = 8e-04);
MVP
MPC
2.3
ClinPred
D
GERP RS
Varity_R
gMVP
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