rs267608490

chrX-18584312-C-AchrX-18584312-C-GchrX-18584312-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001323289.2(CDKL5):c.513C>A(p.Tyr171Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. Y171Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: CDKL5 NM_001323289.2 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 0.868

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-18584312-C-A is Pathogenic according to our data. Variant chrX-18584312-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 143822.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKL5	NM_001323289.2	c.513C>A	p.Tyr171Ter	stop_gained	8/18	ENST00000623535.2
CDKL5	NM_001037343.2	c.513C>A	p.Tyr171Ter	stop_gained	9/22
CDKL5	NM_003159.3	c.513C>A	p.Tyr171Ter	stop_gained	8/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKL5	ENST00000623535.2	c.513C>A	p.Tyr171Ter	stop_gained	8/18	1	NM_001323289.2	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

Developmental and epileptic encephalopathy, 2 Pathogenic:2

Pathogenic, no assertion criteria provided	curation	RettBASE	Mar 13, 2014	Early truncation, partial loss the phophorylation site -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

CDKL5 disorder Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Mar 09, 2021

The p.Tyr171* variant in CDKL5 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.Tyr171* variant in CDKL5 has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with CDKL5 disorder (PMID 23583054) (PM6. This variant has been observed in at least 1 other individual with CDKL5 disorder (ClinVar) (PS4_Supporting). This variant was absent from gnomAD (PM2_ Supporting). In summary, p.Tyr171* variant in CDKL5 is classified as Pathogenic for CDKL5 disorder based on the ACMG/AMP criteria (PVS1, PM6, PM2_Supporting, PS4_Supporting). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2017

The c.513 C>A variant, resulting in the Y171X nonsense variant in the CDKL5 gene, has beenreported previously as a de novo finding in a male with early-onset epilepsy (Mirzaa et al., 2013).This variant is predicted to cause loss of normal protein function either through protein truncation ornonsense-mediated mRNA decay. This variant is not observed in large population cohorts (Lek et al.,2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Additionally, a differentnucleotide substitution (c.513 C>G) that also results in the Y171X nonsense variant was previouslyidentified in a female with features of a CDKL5-related disorder (Sartori et al., 2011). We interpretY171X as a pathogenic variant. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 28, 2023

This sequence change creates a premature translational stop signal (p.Tyr171*) in the CDKL5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CDKL5 are known to be pathogenic (PMID: 22872100). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of CDKL5-related conditions (PMID: 23583054, 29455050). ClinVar contains an entry for this variant (Variation ID: 143822). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
Cadd	Pathogenic	34
Dann	Uncertain	1.0
FATHMM_MKL	Uncertain	0.85	D
MutationTaster	Benign	1.0	A;A
Vest4		0.83
GERP RS		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.39		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.39		Position offset: -4

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

Publications

LitVar

Other links and lift over

dbSNP: rs267608490; hg19: chrX-18602432;