rs267608650

chrX-18609464-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PM2 PP3_Strong PP5_Moderate

The NM_001323289.2(CDKL5):c.2047-1G>A variant causes a splice acceptor 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. 2/2 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
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:3 O:1
• Conservation: PhyloP100: 9.31

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Splicing 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
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-18609464-G-A is Pathogenic according to our data. Variant chrX-18609464-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 156077.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKL5	NM_001323289.2	c.2047-1G>A		splice_acceptor_variant		ENST00000623535.2
CDKL5	NM_001037343.2	c.2047-1G>A		splice_acceptor_variant
CDKL5	NM_003159.3	c.2047-1G>A		splice_acceptor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKL5	ENST00000623535.2	c.2047-1G>A		splice_acceptor_variant		1	NM_001323289.2	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2004

- -

Atypical Rett syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

curation

RettBASE

Mar 13, 2014

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

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 24, 2020

For these reasons, this variant has been classified as Pathogenic. 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). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 15492925). 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). This variant is not present in population databases (ExAC no frequency). 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. -

not provided Other:1

not provided, flagged submission

literature only

RettBASE

-

- -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	D;D
GERP RS		6.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs267608650; hg19: chrX-18627584;