NM_001323289.2:c.506_507delCA

Variant names:

• chrX-18584301-TAC-T
• rs786204987
• NM_001323289.2:c.506_507delCA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001323289.2(CDKL5):​c.506_507delCA​(p.Thr169ArgfsTer36) 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T169T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: CDKL5 NM_001323289.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.32
• Publications: 1 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 18 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-18584301-TAC-T is Pathogenic according to our data. Variant chrX-18584301-TAC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 189592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.506_507delCA	p.Thr169ArgfsTer36	frameshift_variant	Exon 8 of 18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.506_507delCA	p.Thr169ArgfsTer36	frameshift_variant	Exon 9 of 22		NP_001032420.1
CDKL5	NM_003159.3	c.506_507delCA	p.Thr169ArgfsTer36	frameshift_variant	Exon 8 of 21		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.506_507delCA	p.Thr169ArgfsTer36	frameshift_variant	Exon 8 of 18	1	NM_001323289.2	ENSP00000485244.1

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

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

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: 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 pathogenic. At least the following criteria are met: Predicted to result in loss of function, and LOF is a known mechanism of disease (PVS1). This variant is absent from gnomAD v4 (PM2_Supporting). Has been observed in at least 2 individuals with phenotypes consistent with CDKL5 disorder (PS4_Supporting). PMID: 23064044 PMID: 22872100 Variation ID: 189592 -

CDKL5-related disorder Pathogenic:1

Jul 11, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CDKL5 c.506_507delCA variant is predicted to result in a frameshift and premature protein termination (p.Thr169Argfs*36). To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating it is rare. Frameshift variants in CDKL5 are expected to be pathogenic, and a similar variant (c.503_504del p.Y168YfsX204) was reported to be de novo in an individual with developmental and epileptic encephalopathy (Raymond et al 2013. PubMed ID: 23064044). The c.506_507delCA (p.Thr169Argfs*36) variant is interpreted as pathogenic. -

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

Dec 30, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Thr169Argfs*36) in the CDKL5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CDKL5 are known to be pathogenic (PMID: 22872100). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of epileptic encephalopathy (PMID: 23064044). This variant is also known as c.503_504del. ClinVar contains an entry for this variant (Variation ID: 189592). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.3
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs786204987; hg19: chrX-18602421;