rs786204983

Variant names:

• chrX-18579843-TTTAGAATATGC-T
• rs786204983
• NM_001323289.2:c.283-3_290delTAGAATATGCT

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_001323289.2(CDKL5):​c.283-3_290delTAGAATATGCT​(p.Asn95fs) variant causes a frameshift, splice acceptor, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: CDKL5 NM_001323289.2 frameshift, splice_acceptor, splice_region, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 10.0
• Publications: 4 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 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant X-18579843-TTTAGAATATGC-T is Pathogenic according to our data. Variant chrX-18579843-TTTAGAATATGC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 189585.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.283-3_290delTAGAATATGCT	p.Asn95fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 6 of 18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.283-3_290delTAGAATATGCT	p.Asn95fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 7 of 22		NP_001032420.1
CDKL5	NM_003159.3	c.283-3_290delTAGAATATGCT	p.Asn95fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 6 of 21		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.283-4_289delTTAGAATATGC	p.Asn95fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 6 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:3

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

Hagebeuk et al 2013 showed that deletion affects splice site of exon 6, leading of exon 6 skipping in the mRNA and the shift in reading frame causes a truncated protein product -

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). Has been observed in at least 2 individuals with phenotypes consistent with CDKL5 disorder (PS4_Supporting). PMID: 23151060 PMID: 21765152 This variant is absent from gnomAD v4 (PM2_Supporting). -

Atypical Rett syndrome Pathogenic:1

Mar 13, 2014

RettBASE

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

Hagebeuk et al 2013 showed that deletion affects splice site of exon 6, leading of exon 6 skipping in the mRNA and the shift in reading frame causes a truncated protein product -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		10
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: rs786204983; hg19: chrX-18597963;