rs1555951997

Variant names:

• chrX-18604218-AAGT-A
• rs1555951997
• NM_001323289.2:c.1296_1298delGTA

Variant summary

Our verdict is Uncertain significance. The variant received 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 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance reviewed by expert panel U:3
• Conservation: PhyloP100: 8.94
• Publications: 0 publications found

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]

CDKL5 Gene-Disease associations (from GenCC):

• CDKL5 disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 2

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• atypical Rett syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• precocious puberty

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001323289.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKL5	NM_001323289.2	MANE Select	c.1296_1298delGTA	p.Lys432_Tyr433delinsAsn	disruptive_inframe_deletion	Exon 12 of 18	NP_001310218.1	O76039-2
	CDKL5	NM_001037343.2		c.1296_1298delGTA	p.Lys432_Tyr433delinsAsn	disruptive_inframe_deletion	Exon 13 of 22	NP_001032420.1	O76039-1
	CDKL5	NM_003159.3		c.1296_1298delGTA	p.Lys432_Tyr433delinsAsn	disruptive_inframe_deletion	Exon 12 of 21	NP_003150.1	O76039-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKL5	ENST00000623535.2	TSL:1 MANE Select	c.1296_1298delGTA	p.Lys432_Tyr433delinsAsn	disruptive_inframe_deletion	Exon 12 of 18	ENSP00000485244.1	O76039-2
	CDKL5	ENST00000379989.6	TSL:1	c.1296_1298delGTA	p.Lys432_Tyr433delinsAsn	disruptive_inframe_deletion	Exon 13 of 22	ENSP00000369325.3	O76039-1
	CDKL5	ENST00000379996.7	TSL:1	c.1296_1298delGTA	p.Lys432_Tyr433delinsAsn	disruptive_inframe_deletion	Exon 12 of 21	ENSP00000369332.3	O76039-1

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

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	-	CDKL5 disorder (1)
-	1	-	Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.9

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

Other links and lift over

dbSNP: rs1555951997; hg19: chrX-18622338;