X-18628374-C-T

Position:

• chrX-18628374-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM6 PVS1 PP4 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The p.Gln834Ter variant in CDKL5 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.Gln834Ter variant in CDKL5 is absent from gnomAD v4.1 (PM2_Supporting). The p.Gln834Ter variant in CDKL5 has been reported in an individual with a clinical phenotype suggestive of CDKL5 disorder (PMID:16813600) (PP4). The p.Gln834Ter variant in CDKL5 occurs in the de novo state (biological parentage unconfirmed) in this individual (PM6). In summary, the p.Gln834Ter variant in CDKL5 is classified as Pathogenic for CDKL5 disorder based on the ACMG/AMP criteria (PVS1, PM2_Supporting, PP4, PM6). LINK:https://erepo.genome.network/evrepo/ui/classification/CA121519/MONDO:0100039/034

• Frequency: Genomes: not found (cov: 23)
• Consequence: CDKL5 ENST00000623535.2 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:5 U:1
• Conservation: PhyloP100: 7.38

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 12 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.2500C>T	p.Gln834Ter	stop_gained	18/18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.2500C>T	p.Gln834Ter	stop_gained	19/22		NP_001032420.1
CDKL5	NM_003159.3	c.2500C>T	p.Gln834Ter	stop_gained	18/21		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.2500C>T	p.Gln834Ter	stop_gained	18/18	1	NM_001323289.2	ENSP00000485244	P1
CDKL5	ENST00000379989.6	c.2500C>T	p.Gln834Ter	stop_gained	19/22	1		ENSP00000369325
CDKL5	ENST00000379996.7	c.2500C>T	p.Gln834Ter	stop_gained	18/21	1		ENSP00000369332
CDKL5	ENST00000674046.1	c.2623C>T	p.Gln875Ter	stop_gained	19/19			ENSP00000501174

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

CDKL5 disorder Pathogenic:2

Pathogenic, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Oct 30, 2024	The p.Gln834Ter variant in CDKL5 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.Gln834Ter variant in CDKL5 is absent from gnomAD v4.1 (PM2_Supporting). The p.Gln834Ter variant in CDKL5 has been reported in an individual with a clinical phenotype suggestive of CDKL5 disorder (PMID: 16813600) (PP4). The p.Gln834Ter variant in CDKL5 occurs in the de novo state (biological parentage unconfirmed) in this individual (PM6). In summary, the p.Gln834Ter variant in CDKL5 is classified as Pathogenic for CDKL5 disorder based on the ACMG/AMP criteria (PVS1, PM2_Supporting, PP4, PM6). -
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). Has been observed in at least 3 individuals with phenotypes consistent with CDKL5 disorder (PS4_Moderate). PubMed: 16813600‚ 18790821, Variation ID: 11500 This variant is absent from gnomAD v4 (PM2_Supporting). -

Developmental and epileptic encephalopathy, 2 Pathogenic:1 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2006	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant c.2500C>T (p.Gln834Ter) in CDKL5 has been observed in affected individuals in literature (Nectoux J et.al.,2006). This variant has been reported to the ClinVar database as Pathogenic. The variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The nucleotide change in CDKL5 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic . -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 18, 2023

This sequence change creates a premature translational stop signal (p.Gln834*) in the CDKL5 gene. However, it is currently unclear if variants that occur in this region of the gene cause disease. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with CDKL5-related conditions (PMID: 16813600). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 11500). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	37
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	1.0	D
MutationTaster	Benign	1.0	A;A
Vest4		0.98
GERP RS		5.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs122460158; hg19: chrX-18646494;