X-18628404-C-CA

Position:

• chrX-18628404-C-CA

Variant summary

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

The NM_001323289.2(CDKL5):​c.2531dup​(p.His844GlnfsTer85) 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 no assertion criteria provided P:1
• Conservation: PhyloP100: 6.99

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. There are 20 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-18628404-C-CA is Pathogenic according to our data. Variant chrX-18628404-C-CA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189582.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.2531dup	p.His844GlnfsTer85	frameshift_variant	18/18	ENST00000623535.2
CDKL5	NM_001037343.2	c.2531dup	p.His844GlnfsTer66	frameshift_variant	19/22
CDKL5	NM_003159.3	c.2531dup	p.His844GlnfsTer66	frameshift_variant	18/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKL5	ENST00000623535.2	c.2531dup	p.His844GlnfsTer85	frameshift_variant	18/18	1	NM_001323289.2	P1
CDKL5	ENST00000379989.6	c.2531dup	p.His844GlnfsTer66	frameshift_variant	19/22	1
CDKL5	ENST00000379996.7	c.2531dup	p.His844GlnfsTer66	frameshift_variant	18/21	1
CDKL5	ENST00000674046.1	c.2654dup	p.His885GlnfsTer85	frameshift_variant	19/19

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided 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)		0.010		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: rs786204980; hg19: chrX-18646524;