X-18579965-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001323289.2(CDKL5):c.400C>T(p.Arg134Ter) 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
2
2
1
Clinical Significance
Conservation
PhyloP100: 2.27
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-18579965-C-T is Pathogenic according to our data. Variant chrX-18579965-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 143820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18579965-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDKL5 | NM_001323289.2 | c.400C>T | p.Arg134Ter | stop_gained | 6/18 | ENST00000623535.2 | |
CDKL5 | NM_001037343.2 | c.400C>T | p.Arg134Ter | stop_gained | 7/22 | ||
CDKL5 | NM_003159.3 | c.400C>T | p.Arg134Ter | stop_gained | 6/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDKL5 | ENST00000623535.2 | c.400C>T | p.Arg134Ter | stop_gained | 6/18 | 1 | NM_001323289.2 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD3 genomes
?
Cov.:
23
GnomAD4 exome Cov.: 26
GnomAD4 exome
Cov.:
26
GnomAD4 genome ? Cov.: 23
GnomAD4 genome
?
Cov.:
23
ClinVar
Significance: 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 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 06, 2020 | 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 in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 22678952, 21318334, 22670135, 28837158, 25525159, 27334371, 23064044, 30898514, 30776697, 31232219, 25657822, 31313283) - |
Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 23, 2022 | This variant is also known as chrX:18598085:C/T. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 143820). This premature translational stop signal has been observed in individual(s) with clinical features of CDKL5-related conditions (PMID: 21318334, 27334371). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg134*) 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
Uncertain
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