rs267608663

Variant names:

• chrX-18628467-C-T
• rs267608663
• NM_001323289.2:c.2593C>T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_001323289.2(CDKL5):​c.2593C>T​(p.Gln865*) variant causes a stop gained change. 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 (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: CDKL5 NM_001323289.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.41

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 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.101 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-18628467-C-T is Pathogenic according to our data. Variant chrX-18628467-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 143808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.2593C>T	p.Gln865*	stop_gained	Exon 18 of 18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.2593C>T	p.Gln865*	stop_gained	Exon 19 of 22		NP_001032420.1
CDKL5	NM_003159.3	c.2593C>T	p.Gln865*	stop_gained	Exon 18 of 21		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.2593C>T	p.Gln865*	stop_gained	Exon 18 of 18	1	NM_001323289.2	ENSP00000485244.1
CDKL5	ENST00000379989.6	c.2593C>T	p.Gln865*	stop_gained	Exon 19 of 22	1		ENSP00000369325.3
CDKL5	ENST00000379996.7	c.2593C>T	p.Gln865*	stop_gained	Exon 18 of 21	1		ENSP00000369332.3
CDKL5	ENST00000674046.1	c.2716C>T	p.Gln906*	stop_gained	Exon 19 of 19			ENSP00000501174.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 2 Pathogenic:2

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 13, 2014

RettBASE

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

Truncation causing loss of C-terminus -

Inborn genetic diseases Pathogenic:1

Mar 21, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q865* pathogenic mutation (also known as c.2593C>T), located in coding exon 17 of the CDKL5 gene, results from a C to T substitution at nucleotide position 2593. This changes the amino acid from a glutamine to a stop codon within coding exon 17. This mutation was detected as a de novo occurrence in a male individual with infantile spasms, various types of refractory seizures, as well as hypsarrhythmia and multifocal bilateral interictal epileptiform discharged on electroencephalogram (EEG) (Moseley BD et al. Pediatr. Neurol., 2012 Feb;46:101-5). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

CDKL5 disorder Pathogenic:1

Sep 16, 2024

Centre for Population Genomics, CPG

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

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 has been identified as a de novo occurrence in an individual with CDKL5 disorder without confirmation of paternity and maternity (PM6, PMID: 23583054). This variant is absent from gnomAD (PM2_Supporting). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	37
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.96	D
Vest4		0.86
GERP RS		4.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs267608663; hg19: chrX-18646587;