rs1555955290

Positions:

• chrX-18628700-CAG-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.2828_2829delGA​(p.Arg943fs) 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 21)
• Consequence: CDKL5 NM_001323289.2 frameshift
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.51

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 0.0191 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-18628700-CAG-C is Pathogenic according to our data. Variant chrX-18628700-CAG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 441534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.2828_2829delGA	p.Arg943fs	frameshift_variant	18/18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.2713+115_2713+116delGA		intron_variant			NP_001032420.1
CDKL5	NM_003159.3	c.2713+115_2713+116delGA		intron_variant			NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.2828_2829delGA	p.Arg943fs	frameshift_variant	18/18	1	NM_001323289.2	ENSP00000485244.1
CDKL5	ENST00000379989.6	c.2713+115_2713+116delGA		intron_variant		1		ENSP00000369325.3
CDKL5	ENST00000379996.7	c.2713+115_2713+116delGA		intron_variant		1		ENSP00000369332.3
CDKL5	ENST00000674046.1	c.2951_2952delGA	p.Arg984fs	frameshift_variant	19/19			ENSP00000501174.1

Frequencies

GnomAD3 genomes Cov.: 21

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

GnomAD4 genome Cov.: 21

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 2 Pathogenic:3

Pathogenic, no assertion criteria provided	research	ITMI	Sep 05, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 24, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Jan 24, 2022	- -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 07, 2023

This sequence change falls in intron 18 of the CDKL5 gene. It does not directly change the encoded amino acid sequence of the CDKL5 protein on the NM_003159.2 transcript. This variant is also known as NM_001323289.1:c.2828_2829del (p.Arg943Asnfs*11). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 18 amino acids of the CDKL5 protein on this alternate transcript. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of CDKL5-related conditions (PMID: 29444904). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 441534). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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

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: rs1555955290; hg19: chrX-18646820;