rs1555950494

chrX-18588122-TC-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001323289.2(CDKL5):c.725del(p.Pro242LeufsTer25) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: CDKL5 NM_001323289.2 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.56

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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-18588122-TC-T is Pathogenic according to our data. Variant chrX-18588122-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 533390.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKL5	NM_001323289.2	c.725del	p.Pro242LeufsTer25	frameshift_variant	9/18	ENST00000623535.2
CDKL5	NM_001037343.2	c.725del	p.Pro242LeufsTer25	frameshift_variant	10/22
CDKL5	NM_003159.3	c.725del	p.Pro242LeufsTer25	frameshift_variant	9/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKL5	ENST00000623535.2	c.725del	p.Pro242LeufsTer25	frameshift_variant	9/18	1	NM_001323289.2	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 12, 2017

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in CDKL5 are known to be pathogenic (PMID: 22872100). This variant has not been reported in the literature in individuals with CDKL5-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Pro242Leufs*25) in the CDKL5 gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555950494; hg19: chrX-18606242;