rs62653623

Variant names:

• chrX-18575383-C-T
• rs62653623
• NM_001323289.2:c.175C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001323289.2(CDKL5):​c.175C>T​(p.Arg59*) variant causes a stop gained 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. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: CDKL5 NM_001323289.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 7.91
• Publications: 34 publications found

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 Gene-Disease associations (from GenCC):

• CDKL5 disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 2

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• atypical Rett syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• precocious puberty

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 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-18575383-C-T is Pathogenic according to our data. Variant chrX-18575383-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 143783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.175C>T	p.Arg59*	stop_gained	Exon 5 of 18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.175C>T	p.Arg59*	stop_gained	Exon 6 of 22		NP_001032420.1
CDKL5	NM_003159.3	c.175C>T	p.Arg59*	stop_gained	Exon 5 of 21		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.175C>T	p.Arg59*	stop_gained	Exon 5 of 18	1	NM_001323289.2	ENSP00000485244.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 2 Pathogenic:3

Feb 01, 2024

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg59*) 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 CDKL5-related conditions (PMID: 16611748, 23583054, 31313283). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 143783). For these reasons, this variant has been classified as Pathogenic. -

Mar 13, 2014

RettBASE

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

In vitro study (Ricciardi et al 2009) shows abnormal nuclear speckles -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

May 22, 2018

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in the heterozygous state in a female with epileptic encephalopathy and severe intellectual disability (PMID: 16611748), and in heterozygous state in a female with severe intellectual disability, hand stereotypies, and deceleration of head growth (PMID: 22678952); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Published functional studies demonstrate a damaging effect, with mouse models exhibiting autistic-like behaviors (PMID: 31201320, 30952813); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20493745, 21502606, 23238081, 29455050, 23583054, 19740913, 29961513, 31232219, 30952813, 31539537, 31456437, 31313283, 33905871, 33047306, 22678952, 16611748, 31201320) -

CDKL5 disorder Pathogenic:1

Aug 21, 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 5 individuals with phenotypes consistent with CDKL5 disorder (PS4). PMID 16611748 ClinVar Variation ID: 143783 -

Atypical Rett syndrome Pathogenic:1

Mar 13, 2014

RettBASE

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

In vitro study (Ricciardi et al 2009) shows abnormal nuclear speckles -

CDKL5-related disorder Pathogenic:1

Feb 01, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CDKL5 c.175C>T variant is predicted to result in premature protein termination (p.Arg59*). This variant has been reported in multiple male and female individuals with developmental and epileptic encephalopathy and in all patients where parents were available for testing the variant was reported to be de novo (Archer et al. 2006. PubMed ID: 16611748; Castrén et al. 2010. PubMed ID: 20493745; Klein et al. 2011. PubMed ID: 21502606; Bahi-Buisson et al. 2012. PubMed ID: 22678952; Mirzaa et al. 2013. PubMed ID: 23583054; Almomen et al. 2018. PubMed ID: 29961513). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in CDKL5 are expected to be pathogenic. This variant is interpreted as pathogenic. -

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

Feb 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 143783). This premature translational stop signal has been observed in individual(s) with CDKL5-related conditions (PMID: 16611748, 23583054, 31313283). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg59*) 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	38
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		7.9
Vest4		0.88
GERP RS		5.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs62653623; hg19: chrX-18593503; COSMIC: COSV66112951;