rs267608501

Positions:

• chrX-18587986-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001323289.2(CDKL5):​c.587C>T​(p.Ser196Leu) variant causes a missense 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. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: CDKL5 NM_001323289.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 7.57

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]

CDKL5 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant X-18587986-C-T is Pathogenic according to our data. Variant chrX-18587986-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 143827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18587986-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.587C>T	p.Ser196Leu	missense_variant	9/18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.587C>T	p.Ser196Leu	missense_variant	10/22		NP_001032420.1
CDKL5	NM_003159.3	c.587C>T	p.Ser196Leu	missense_variant	9/21		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.587C>T	p.Ser196Leu	missense_variant	9/18	1	NM_001323289.2	ENSP00000485244.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 15, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 19, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22872100, 22670135, 35153983, 22779007, 20397747, 25657822, 22264704, 31791873, 34489640, 33436160, 33047306) -

Developmental and epileptic encephalopathy, 2 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Mar 14, 2017	- -
Likely pathogenic, no assertion criteria provided	curation	RettBASE	Mar 13, 2014	In silico prediction: SIFT = deleterious, MutationTaster = disease-causing, PolyPhen2 = probably damaging, AlignGVGD = pathogenic (C65) -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	May 04, 2022	The heterozygous p.Ser196Leu variant in CDKL5 was identified by our study in 1 individual with early infantile epileptic encephalopathy 2. Trio exome analysis showed this variant to be de novo, and this variant is also assumed de novo in 3 individuals in the literature, but maternity and paternity have not been confirmed (PMID: 20397747, 33436160). The variant has been reported in at least 8 individuals of unknown ethnicity with early infantile epileptic encephalopathy 2 (PMID: 20397747, 31791873, 22872100, 22264704, 33436160, 24375629), but was absent from large population studies. This variant has also been reported in ClinVar (Variation ID: 143827) as pathogenic by Genetic Services Laboratory, University of Chicago, Neurogenetics Laboratory - MEYER, AOU Meyer, and Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, and as likely pathogenic by Invitae and RettBASE. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS2, PS4_moderate, PM2 (Richards 2015). -

CDKL5 disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

Centre for Population Genomics, CPG

Sep 05, 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: This variant has been identified as a de novo occurrence in at least 2 individuals with CDKL5 disorder, without confirmation of paternity and maternity (PM6_Strong, PMID: 20397747, PMID: 33436160, ClinVar Variation ID: 143827). Has been observed in at least 5 individuals with phenotypes consistent with CDKL5 disorder (PS4, PMID: 31791873, 31791873, ClinVar Variation ID: 143827). This variant is absent from gnomAD (PM2_Supporting). -

Epileptic encephalopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Neurogenetics Laboratory - MEYER, AOU Meyer

Nov 16, 2016

- -

Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 27, 2023

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 196 of the CDKL5 protein (p.Ser196Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with epileptic encephalopathy (PMID: 20397747; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 143827). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CDKL5 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.26	T;T;.;T;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D;D;D;D;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Pathogenic	3.0	M;.;.;M;.;M
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-4.0	D;.;.;D;.;.
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0010	D;.;.;D;.;.
Sift4G	Uncertain	0.0020	D;.;.;D;D;D
Polyphen		1.0	D;.;.;D;.;.
Vest4		0.97
MutPred		0.96		Loss of catalytic residue at S196 (P = 0.0265);Loss of catalytic residue at S196 (P = 0.0265);Loss of catalytic residue at S196 (P = 0.0265);Loss of catalytic residue at S196 (P = 0.0265);Loss of catalytic residue at S196 (P = 0.0265);Loss of catalytic residue at S196 (P = 0.0265);
MVP		0.94
MPC		2.1
ClinPred		0.99	D
GERP RS		6.1
Varity_R		0.98
gMVP		0.99

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: rs267608501; hg19: chrX-18606106; COSMIC: COSV66112168;