rs267608395

Positions:

• chrX-18604599-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001323289.2(CDKL5):​c.1675C>T​(p.Arg559*) 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: CDKL5 NM_001323289.2 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 2.28

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]

ACMG classification

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-18604599-C-T is Pathogenic according to our data. Variant chrX-18604599-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 143781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18604599-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.1675C>T	p.Arg559*	stop_gained	12/18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.1675C>T	p.Arg559*	stop_gained	13/22		NP_001032420.1
CDKL5	NM_003159.3	c.1675C>T	p.Arg559*	stop_gained	12/21		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.1675C>T	p.Arg559*	stop_gained	12/18	1	NM_001323289.2	ENSP00000485244.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 2 Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 18, 2017	- -
Pathogenic, no assertion criteria provided	curation	RettBASE	Mar 13, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Pathogenic, criteria provided, single submitter	not provided	Institute of Human Genetics, University Hospital of Duesseldorf	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Génétique des Maladies du Développement, Hospices Civils de Lyon	Jul 11, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Oct 14, 2019	This variant was identified as hemizygous -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 2024	Mosaic variant in patients with seizures and intellectual disability previously tested at GeneDx and in the published literature (PMID: 28837158); 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 (gnomAD); This variant is associated with the following publications: (PMID: 27823948, 22670135, 22779007, 23064044, 25525159, 19161156, 27770071, 27081548, 23583054, 30928302, 30460546, 22872100, 21770923, 33951346, 33047306, 31440721, 35982159, 33057194, 37201242, 28837158, 31313283) -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	Sep 26, 2016	- -

CDKL5 disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

Centre for Population Genomics, CPG

Aug 21, 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 pathogenic. At least the following criteria are met: Predicted to result in loss of function, and LOF is a known mechanism of disease (PVS1). This variant is absent from gnomAD v4 (PM2_Supporting). Has been observed in at least 2 individuals with phenotypes consistent with CDKL5 disorder (PS4_Supporting). PMID 19161156 Variation ID: 143781 -

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

Labcorp Genetics (formerly Invitae), Labcorp

Apr 24, 2021

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in CDKL5 are known to be pathogenic (PMID: 22872100). This variant has been observed in individuals with epilepsy (PMID: 27770071, 27823948, 22872100) and to be de novo in an individual affected with suspected early onset encephalopathy (PMID: 19161156). ClinVar contains an entry for this variant (Variation ID: 143781). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg559*) in the CDKL5 gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	34
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.95	D
Vest4		0.95
GERP RS		3.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs267608395; hg19: chrX-18622719;