Genetic Variant CDKL5:c.464-2A>G (chrX-18584261-A-G) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_001323289.2(CDKL5):c.464-2A>G 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)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

CDKL5
NM_001323289.2 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3O:1

Conservation

PhyloP100: 9.32

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.031564344 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.6, offset of 21, new splice context is: ttttgctcgtaatctgtcAGaag. Cryptic site results in inframe 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-18584261-A-G is Pathogenic according to our data. Variant chrX-18584261-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 156090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18584261-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CDKL5	NM_001323289.2 link	c.464-2A>G	splice_acceptor_variant, intron_variant	Intron 7 of 17	ENST00000623535.2	NP_001310218.1	O76039-2
CDKL5	NM_001037343.2 link	c.464-2A>G	splice_acceptor_variant, intron_variant	Intron 8 of 21		NP_001032420.1	O76039-1
CDKL5	NM_003159.3 link	c.464-2A>G	splice_acceptor_variant, intron_variant	Intron 7 of 20		NP_003150.1	O76039-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2 link	c.464-2A>G		splice_acceptor_variant, intron_variant	Intron 7 of 17	1	NM_001323289.2	ENSP00000485244.1		O76039-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1070373

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

339855

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

Leads to exon 8 skipping, r.464_554del -

Inborn genetic diseases

Pathogenic:1

Feb 19, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.464-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 7 in the CDKL5 gene. This mutation (denoted as IVS7-2A>G) was first described in an infant with microcephaly, severe developmental delay, failure to thrive, hand stereotypies, variable tone, and dysmorphic facial features, who met clinical criteria for Rett syndrome but whose features more closely resembled severe epileptic encephalopathy. Amplification of cDNA revealed 2 different RT-PCR products, and sequencing of the smaller product was consistent with loss of exon 8 (coding exon 7) (Evans JC et al. Eur. J. Hum. Genet., 2005 Oct;13:1113-20). This mutation has also been observed in an individual with early onset epileptic encephalopathy (Carvill GL et al. Nat. Genet., 2013 Jul;45:825-30). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -

CDKL5 disorder

Pathogenic:1

Sep 20, 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). PubMed: 16015284‚ 23708187, Variation ID: 156090. -

not provided

Other:1

RettBASE

Significance: not provided

Review Status: flagged submission

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

DANN

Uncertain

0.99

FATHMM_MKL

Pathogenic

0.99

GERP RS

5.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.76

Position offset: -27

DS_AL_spliceai

0.99

Position offset: 2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over