rs786204983

Positions:

• chrX-18579843-TTTAGAATATGC-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP3 PP5

The NM_001323289.2(CDKL5):​c.283-3_290del variant causes a splice acceptor, coding sequence, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 22)
• Consequence: CDKL5 NM_001323289.2 splice_acceptor, coding_sequence, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 10.0

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 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant X-18579843-TTTAGAATATGC-T is Pathogenic according to our data. Variant chrX-18579843-TTTAGAATATGC-T is described in ClinVar as [Pathogenic]. Clinvar id is 189585.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKL5	NM_001323289.2	c.283-3_290del		splice_acceptor_variant, coding_sequence_variant, intron_variant	6/18	ENST00000623535.2
CDKL5	NM_001037343.2	c.283-3_290del		splice_acceptor_variant, coding_sequence_variant, intron_variant	7/22
CDKL5	NM_003159.3	c.283-3_290del		splice_acceptor_variant, coding_sequence_variant, intron_variant	6/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKL5	ENST00000623535.2	c.283-3_290del		splice_acceptor_variant, coding_sequence_variant, intron_variant	6/18	1	NM_001323289.2	P1

Frequencies

GnomAD3 genomes Cov.: 22

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Developmental and epileptic encephalopathy, 2 Pathogenic:1

Pathogenic, no assertion criteria provided

curation

RettBASE

Mar 13, 2014

Hagebeuk et al 2013 showed that deletion affects splice site of exon 6, leading of exon 6 skipping in the mRNA and the shift in reading frame causes a truncated protein product -

Atypical Rett syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

curation

RettBASE

Mar 13, 2014

Hagebeuk et al 2013 showed that deletion affects splice site of exon 6, leading of exon 6 skipping in the mRNA and the shift in reading frame causes a truncated protein product -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs786204983; hg19: chrX-18597963;