rs267608663

chrX-18628467-C-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.Gln865Ter) 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:3
• 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. There are 16 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/exons	MANE	UniProt
CDKL5	NM_001323289.2	c.2593C>T	p.Gln865Ter	stop_gained	18/18	ENST00000623535.2
CDKL5	NM_001037343.2	c.2593C>T	p.Gln865Ter	stop_gained	19/22
CDKL5	NM_003159.3	c.2593C>T	p.Gln865Ter	stop_gained	18/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKL5	ENST00000623535.2	c.2593C>T	p.Gln865Ter	stop_gained	18/18	1	NM_001323289.2	P1
CDKL5	ENST00000379989.6	c.2593C>T	p.Gln865Ter	stop_gained	19/22	1
CDKL5	ENST00000379996.7	c.2593C>T	p.Gln865Ter	stop_gained	18/21	1
CDKL5	ENST00000674046.1	c.2716C>T	p.Gln906Ter	stop_gained	19/19

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 2 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Pathogenic, no assertion criteria provided	curation	RettBASE	Mar 13, 2014	Truncation causing loss of C-terminus -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 21, 2017

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. -

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
MutationTaster	Benign	1.0	A;A
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;