NM_001323289.2:c.2363_2367delAGAAA

Variant names:

• chrX-18619951-GAAGAA-G
• rs267608655
• NM_001323289.2:c.2363_2367delAGAAA

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001323289.2(CDKL5):​c.2363_2367delAGAAA​(p.Lys788IlefsTer11) 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 (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: CDKL5 NM_001323289.2 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.36
• 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: Pathogenic. The variant received 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-18619951-GAAGAA-G is Pathogenic according to our data. Variant chrX-18619951-GAAGAA-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 143802.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKL5	NM_001323289.2	MANE Select	c.2363_2367delAGAAA	p.Lys788IlefsTer11	frameshift	Exon 16 of 18	NP_001310218.1
	CDKL5	NM_001037343.2		c.2363_2367delAGAAA	p.Lys788IlefsTer11	frameshift	Exon 17 of 22	NP_001032420.1
	CDKL5	NM_003159.3		c.2363_2367delAGAAA	p.Lys788IlefsTer11	frameshift	Exon 16 of 21	NP_003150.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKL5	ENST00000623535.2	TSL:1 MANE Select	c.2363_2367delAGAAA	p.Lys788IlefsTer11	frameshift	Exon 16 of 18	ENSP00000485244.1
	CDKL5	ENST00000379989.6	TSL:1	c.2363_2367delAGAAA	p.Lys788IlefsTer11	frameshift	Exon 17 of 22	ENSP00000369325.3
	CDKL5	ENST00000379996.7	TSL:1	c.2363_2367delAGAAA	p.Lys788IlefsTer11	frameshift	Exon 16 of 21	ENSP00000369332.3

Frequencies

GnomAD3 genomes Cov.: 23

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

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 2 Pathogenic:1

Mar 13, 2014

RettBASE

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

CDKL5 disorder Pathogenic:1

Sep 18, 2024

Centre for Population Genomics, CPG

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria. Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as likely pathogenic. At least the following criteria are met: This variant is absent from gnomAD v4 (PM2_Supporting). Predicted to result in loss of function, and LOF is a known mechanism of disease (PVS1).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.4
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs267608655; hg19: chrX-18638071;