rs786204967

chrX-18604168-CAG-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001323289.2(CDKL5):c.1247_1248del(p.Glu416ValfsTer2) variant causes a frameshift change involving the alteration of a conserved nucleotide. 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 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 9.60

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant X-18604168-CAG-C is Pathogenic according to our data. Variant chrX-18604168-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 189554.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chrX-18604168-CAG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKL5	NM_001323289.2	c.1247_1248del	p.Glu416ValfsTer2	frameshift_variant	12/18	ENST00000623535.2
CDKL5	NM_001037343.2	c.1247_1248del	p.Glu416ValfsTer2	frameshift_variant	13/22
CDKL5	NM_003159.3	c.1247_1248del	p.Glu416ValfsTer2	frameshift_variant	12/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKL5	ENST00000623535.2	c.1247_1248del	p.Glu416ValfsTer2	frameshift_variant	12/18	1	NM_001323289.2	P1

Frequencies

GnomAD3 genomes Cov.: 23

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2023	Frameshift 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: 23064044, 27864847, 27779742, 31164858, 30945278, 34229227, 22872100) -
Pathogenic, no assertion criteria provided	curation	RettBASE	Mar 13, 2014	- -

Developmental and epileptic encephalopathy, 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Dec 13, 2023

Criteria applied: PVS1,PM6_STR,PS4,PM2_SUP -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 09, 2015

- -

CDKL5 disorder Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Mar 26, 2021

The p.Glu416Valfs variant in CDKL5 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.Glu416Valfs variant has been observed in at least 5 individuals with CDKL5 disease (PMID: 27779742, 27864847, 23064044, ClinVar Variation ID 189554) (PS4). The p.XX variant in GENE has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with CDKL5 disorder (PMID XX) (PMID 27779742, 27864847) (PM6_strong). This variant is absent from gnomAD (PM2_supporting). In summary, this variant meets criteria to be classified as pathogenic for CDKL5-associated disorder based on the ACMG/AMP criteria applied (PVS1, PS4, PM6_strong, 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

Invitae

Oct 15, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 189554). This variant is also known as c.1245_1246delAG. This premature translational stop signal has been observed in individual(s) with clinical features of CDKL5-related conditions (PMID: 23064044, 27779742, 30945278, 31164858). 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.Glu416Valfs*2) 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: dbNSFP v4.3

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: rs786204967; hg19: chrX-18622288;