rs61753251

Positions:

• chrX-18628508-CCT-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_001323289.2(CDKL5):​c.2635_2636del​(p.Leu879GlufsTer49) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: CDKL5 NM_001323289.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 4.94

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: 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 0.086 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-18628508-CCT-C is Pathogenic according to our data. Variant chrX-18628508-CCT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 143809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18628508-CCT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.2635_2636del	p.Leu879GlufsTer49	frameshift_variant	18/18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.2635_2636del	p.Leu879GlufsTer30	frameshift_variant	19/22		NP_001032420.1
CDKL5	NM_003159.3	c.2635_2636del	p.Leu879GlufsTer30	frameshift_variant	18/21		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.2635_2636del	p.Leu879GlufsTer49	frameshift_variant	18/18	1	NM_001323289.2	ENSP00000485244	P1
CDKL5	ENST00000379989.6	c.2635_2636del	p.Leu879GlufsTer30	frameshift_variant	19/22	1		ENSP00000369325
CDKL5	ENST00000379996.7	c.2635_2636del	p.Leu879GlufsTer30	frameshift_variant	18/21	1		ENSP00000369332
CDKL5	ENST00000674046.1	c.2758_2759del	p.Leu920GlufsTer49	frameshift_variant	19/19			ENSP00000501174

Frequencies

GnomAD3 genomes Cov.: 22

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

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 2 Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	NeuroMeGen, Hospital Clinico Santiago de Compostela	Jan 01, 2018	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2005	- -
Pathogenic, no assertion criteria provided	curation	RettBASE	Mar 13, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	CDKL5: PVS1, PM2, PS4:Moderate -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 30, 2013	The c.2635_2636delCT mutation in the CDKL5 gene has been reported previously in a female patient with early-onset epilepsy, acquired microcephaly, hand apraxia and hypotonia (Scala et al., 2005). The deletion causes a frameshift starting with codon Leucine 879, changes this amino acid to a Glutamic acid residue and creates a premature Stop codon at position 30 of the new reading frame, denoted p.Leu879GlufsX30. This mutation is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay, and is consistent with the diagnosis of a CDKL5-related disorder. The variant is found in EPILEPSY panel(s). -

CDKL5 disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

Centre for Population Genomics, CPG

Sep 19, 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). This variant has been identified as a de novo occurrence in an individual with CDKL5 disorder without confirmation of paternity and maternity (PM6, PMID: 15689447). This variant is absent from gnomAD (PM2_Supporting). -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 06, 2022

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this premature translational stop signal affects CDKL5 function (PMID: 15689447, 18790821). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 143809). This premature translational stop signal has been observed in individual(s) with clinical features of CDKL5 related conditions (PMID: 15689447, 18790821, 22678952). 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.Leu879Glufs*30) in the CDKL5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 152 amino acid(s) of the CDKL5 protein. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs61753251; hg19: chrX-18646628;