chrX-18510818-A-AG

Variant names:

• chrX-18510818-A-AG
• rs267608420
• NM_001323289.2:c.65dupG

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PM2 PP3_Moderate PP5_Very_Strong

The NM_001323289.2(CDKL5):​c.65dupG​(p.Ala23fs) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: CDKL5 NM_001323289.2 frameshift, splice_region
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 8.05
• 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 20 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 479 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-18510818-A-AG is Pathogenic according to our data. Variant chrX-18510818-A-AG is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 143831.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.65dupG	p.Ala23fs	frameshift_variant, splice_region_variant	Exon 3 of 18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.65dupG	p.Ala23fs	frameshift_variant, splice_region_variant	Exon 4 of 22		NP_001032420.1
CDKL5	NM_003159.3	c.65dupG	p.Ala23fs	frameshift_variant, splice_region_variant	Exon 3 of 21		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.65-2_65-1insG		splice_acceptor_variant, intron_variant	Intron 2 of 17	1	NM_001323289.2	ENSP00000485244.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 2 Pathogenic:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CDKL5 disorder Pathogenic:1

Jul 04, 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: Predicted to result in loss of function, and LOF is a known mechanism of disease (PVS1). This variant is absent from gnomAD (PM2_Supporting). -

not provided Other:1

-

RettBASE

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.1
Mutation Taster		=10/90	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.91		Position offset: 1
DS_AL_spliceai		0.95		Position offset: 2

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

Other links and lift over

dbSNP: rs267608420; hg19: chrX-18528938;