X-18604218-AAGT-A

Position:

• chrX-18604218-AAGT-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2_Supporting PM4_Supporting

This summary comes from the ClinGen Evidence Repository: The p.Lys432_Tyr433delinsAsn variant in CDKL5 is absent from gnomAD (PM2_supporting). The p.Lys432_Tyr433delinsAsn variant causes a change in the length of 1 amino acid in the protein due to an in-frame deletion or insertion in a non-repeat region of CDKL5 (PM4_supporting). In summary, p.Lys432_Tyr433delinsAsn variant in CDKL5 is classified as a variant of uncertain significance based on the ACMG/AMP criteria (PM2_supporting, PM4_supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA645373290/MONDO:0100039/016

• Frequency: Genomes: not found (cov: 22)
• Consequence: CDKL5 NM_001323289.2 inframe_deletion
• Clinical Significance: Uncertain significance reviewed by expert panel U:3
• Conservation: PhyloP100: 8.94

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM4: 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.1296_1298del	p.Lys432_Tyr433delinsAsn	inframe_deletion	12/18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.1296_1298del	p.Lys432_Tyr433delinsAsn	inframe_deletion	13/22		NP_001032420.1
CDKL5	NM_003159.3	c.1296_1298del	p.Lys432_Tyr433delinsAsn	inframe_deletion	12/21		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.1296_1298del	p.Lys432_Tyr433delinsAsn	inframe_deletion	12/18	1	NM_001323289.2	ENSP00000485244	P1

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: Uncertain significance

Submissions summary: Uncertain:3

Revision: reviewed by expert panel

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 12, 2015

- -

CDKL5 disorder Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Mar 26, 2021

The p.Lys432_Tyr433delinsAsn variant in CDKL5 is absent from gnomAD (PM2_supporting). The p.Lys432_Tyr433delinsAsn variant causes a change in the length of 1 amino acid in the protein due to an in-frame deletion or insertion in a non-repeat region of CDKL5 (PM4_supporting). In summary, p.Lys432_Tyr433delinsAsn variant in CDKL5 is classified as a variant of uncertain significance based on the ACMG/AMP criteria (PM2_supporting, PM4_supporting). -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 31, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 434662). This variant has not been reported in the literature in individuals affected with CDKL5-related conditions. This variant is not present in population databases (gnomAD no frequency). This variant, c.1296_1298del, results in the deletion of one amino acid(s) of the CDKL5 protein (p.Lys432_Tyr433delinsAsn), but otherwise preserves the integrity of the reading frame. -

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: rs1555951997; hg19: chrX-18622338;