rs267608643
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001323289.2(CDKL5):c.1648C>T(p.Arg550Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 23)
Consequence
CDKL5
NM_001323289.2 stop_gained
NM_001323289.2 stop_gained
Scores
3
1
1
Clinical Significance
Conservation
PhyloP100: 2.73
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]
Genome browser will be placed here
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-18604572-C-T is Pathogenic according to our data. Variant chrX-18604572-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 143780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18604572-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDKL5 | NM_001323289.2 | c.1648C>T | p.Arg550Ter | stop_gained | 12/18 | ENST00000623535.2 | |
CDKL5 | NM_001037343.2 | c.1648C>T | p.Arg550Ter | stop_gained | 13/22 | ||
CDKL5 | NM_003159.3 | c.1648C>T | p.Arg550Ter | stop_gained | 12/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDKL5 | ENST00000623535.2 | c.1648C>T | p.Arg550Ter | stop_gained | 12/18 | 1 | NM_001323289.2 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD3 genomes
?
Cov.:
23
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 23
GnomAD4 genome
?
Cov.:
23
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Developmental and epileptic encephalopathy, 2 Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Undiagnosed Diseases Network, NIH | Jul 30, 2021 | - - |
Pathogenic, no assertion criteria provided | curation | RettBASE | Mar 13, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Sep 01, 2022 | The variant is not observed in the gnomAD v2.1.1 dataset. This stop-gained (nonsense) variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been previously reported as de novo in a similarly affected individual (PMID: 19241098). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000143780 / PMID: 18063413). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Sep 02, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with developmental and epileptic encephalopathy 2 (MIM#300672). (I) 0110 - This gene is associated with X-linked dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by clinical laboratories in ClinVar and identified in individuals with epileptic encephalopathy and early-onset seizures in the literature (PMID: PMID:22678952, PMID:18063413, PMID:33436160, PMID:27599155). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Pathogenic, criteria provided, single submitter | clinical testing | Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille | - | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 01, 2023 | Reported in association with atypical Rett syndrome and CDKL5-related disorders (Pintaudi et al., 2008; Rademacher et al., 2011; Bahi-Buisson et al., 2012); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29264392, 27599155, 25525159, 19241098, 18063413, 21318334, 29655203, 31313283, 31232219, 33714067, 33436160, 33047306, 35153983, 22678952) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2021 | - - |
Atypical Rett syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | curation | RettBASE | Mar 13, 2014 | - - |
Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 27, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 143780). This premature translational stop signal has been observed in individuals with clinical features of CDKL5-related conditions (PMID: 18063413, 21318334, 22678952). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg550*) 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:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A
Vest4
GERP RS
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