rs786204973

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001323289.2(CDKL5):​c.-162-2A>G variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely 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

2
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 4.78
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.3, offset of -26, new splice context is: tgcaaatataaaacttacAGctt. 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-18506933-A-G is Pathogenic according to our data. Variant chrX-18506933-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189565.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CDKL5NM_001323289.2 linkuse as main transcriptc.-162-2A>G splice_acceptor_variant, intron_variant ENST00000623535.2 NP_001310218.1 O76039-2
CDKL5NM_001037343.2 linkuse as main transcriptc.-162-2A>G splice_acceptor_variant, intron_variant NP_001032420.1 O76039-1
CDKL5NM_003159.3 linkuse as main transcriptc.-162-2A>G splice_acceptor_variant, intron_variant NP_003150.1 O76039-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CDKL5ENST00000623535.2 linkuse as main transcriptc.-162-2A>G splice_acceptor_variant, intron_variant 1 NM_001323289.2 ENSP00000485244.1 O76039-2

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
328559
Hom.:
0
Cov.:
3
AF XY:
0.00
AC XY:
0
AN XY:
105131
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.:
23

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 2 Pathogenic:1
Pathogenic, no assertion criteria providedcurationRettBASEMar 13, 2014Splice site mutation causing skipping of exon 2 (loss of AUG codon) -
CDKL5 disorder Pathogenic:1
Likely pathogenic, criteria provided, single submittercurationCentre for Population Genomics, CPGSep 20, 2024This 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: This variant has been identified as a de novo occurrence in an individual with CDKL5 disorder without confirmation of paternity and maternity (PM6, PMID: 19793311). Well-established in vitro or in vivo functional studies strongly supportive of a damaging effect on the protein function (PS3). This variant is absent from gnomAD (PM2_Supporting). -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxNov 08, 2021Observed in hemizygous state in a patient with seizures in the literature (Dimassi et al., 2015); Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts; however, limited data are available (Lek et al., 2016); This variant is associated with the following publications: (PMID: 29264392, 25525159, 22670135, 22779007, 27054081, 19793311) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Uncertain
-0.050
CADD
Benign
22
DANN
Uncertain
0.98

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.84

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.

Other links and lift over

dbSNP: rs786204973; hg19: chrX-18525053; API