rs267608650

Variant names:

• chrX-18609464-G-A
• rs267608650
• NM_001323289.2:c.2047-1G>A

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.2047-1G>A variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: CDKL5 NM_001323289.2 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 9.31
• 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: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 7.6, offset of 1, new splice context is: aatttctttcctgcctcaAGgtg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-18609464-G-A is Pathogenic according to our data. Variant chrX-18609464-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 156077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.2047-1G>A		splice_acceptor intron	N/A	NP_001310218.1
	CDKL5	NM_001037343.2		c.2047-1G>A		splice_acceptor intron	N/A	NP_001032420.1
	CDKL5	NM_003159.3		c.2047-1G>A		splice_acceptor intron	N/A	NP_003150.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKL5	ENST00000623535.2	TSL:1 MANE Select	c.2047-1G>A		splice_acceptor intron	N/A	ENSP00000485244.1
	CDKL5	ENST00000379989.6	TSL:1	c.2047-1G>A		splice_acceptor intron	N/A	ENSP00000369325.3
	CDKL5	ENST00000379996.7	TSL:1	c.2047-1G>A		splice_acceptor intron	N/A	ENSP00000369332.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 2 Pathogenic:1

Dec 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

CDKL5 disorder Pathogenic:1

Sep 16, 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 has been identified as a de novo occurrence in an individual with CDKL5 disorder without confirmation of paternity and maternity (PM6). This variant is absent from gnomAD (PM2_Supporting).

Atypical Rett syndrome Pathogenic:1

Mar 13, 2014

RettBASE

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

Acceptor site of intron 13, activates an alternate splice site r.2047delG

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

Sep 24, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 15492925). This sequence change affects an acceptor splice site in intron 13 of the CDKL5 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with CDKL5-related conditions (PMID: 15492925). In at least one individual the variant was observed to be de novo. This variant is also known as IVS13-1G>A. ClinVar contains an entry for this variant (Variation ID: 156077). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CDKL5 are known to be pathogenic (PMID: 22872100). For these reasons, this variant has been classified as Pathogenic.

not provided Other:1

RettBASE

Significance: not provided

Review Status: flagged submission

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	35
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		9.3
GERP RS		6.1
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.99		Position offset: 2
DS_AL_spliceai		0.99		Position offset: 1

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

Other links and lift over

dbSNP: rs267608650; hg19: chrX-18627584;