X-18604234-A-AC

Position:

• chrX-18604234-A-AC

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM6 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1311dup 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 c.1311dup variant in CDKL5 has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with early onset seizures and infantile spasms (PMID 19793311) (PM6). The c.1311dup variant in CDKL5 is absent from gnomAD v2.1.1 (PM2_supporting). In summary, the c.1311dup variant in CDKL5 is classified as pathogenic for a CDKL5-related disorder based on the ACMG/AMP criteria (PVS1, PM6, PM2_supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA170444/MONDO:0100039/034

• Frequency: Genomes: not found (cov: 23)
• Consequence: CDKL5 NM_001323289.2 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 1.55

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 11 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.1311dup	p.Ser438GlnfsTer25	frameshift_variant	12/18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.1311dup	p.Ser438GlnfsTer25	frameshift_variant	13/22		NP_001032420.1
CDKL5	NM_003159.3	c.1311dup	p.Ser438GlnfsTer25	frameshift_variant	12/21		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.1311dup	p.Ser438GlnfsTer25	frameshift_variant	12/18	1	NM_001323289.2	ENSP00000485244	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

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	Apr 18, 2024	The c.1311dup 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 c.1311dup variant in CDKL5 has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with early onset seizures and infantile spasms (PMID 19793311) (PM6). The c.1311dup variant in CDKL5 is absent from gnomAD v2.1.1 (PM2_supporting). In summary, the c.1311dup variant in CDKL5 is classified as pathogenic for a CDKL5-related disorder based on the ACMG/AMP criteria (PVS1, PM6, PM2_supporting). -
Pathogenic, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Sep 13, 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: 19793311). This variant is absent from gnomAD (PM2_Supporting). -

Atypical Rett syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

curation

RettBASE

Mar 13, 2014

- -

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: rs267608623; hg19: chrX-18622354;