chrX-18588058-T-C

Variant names:

• chrX-18588058-T-C
• rs267608511
• NM_001323289.2:c.659T>C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_001323289.2(CDKL5):​c.659T>C​(p.Leu220Pro) variant causes a missense 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. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L220L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: CDKL5 NM_001323289.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.67
• Publications: 12 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 16 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001323289.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant X-18588058-T-C is Pathogenic according to our data. Variant chrX-18588058-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 143830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18588058-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 143830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18588058-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 143830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18588058-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 143830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18588058-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 143830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18588058-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 143830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18588058-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 143830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18588058-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 143830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18588058-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 143830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18588058-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 143830.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.659T>C	p.Leu220Pro	missense_variant	Exon 9 of 18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.659T>C	p.Leu220Pro	missense_variant	Exon 10 of 22		NP_001032420.1
CDKL5	NM_003159.3	c.659T>C	p.Leu220Pro	missense_variant	Exon 9 of 21		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.659T>C	p.Leu220Pro	missense_variant	Exon 9 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/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

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

In vitro study shows mislocalisation of CDKL5 in the cytoplasm; In silico prediction: SIFT = deleterious, MutationTaster = disease-causing, PolyPhen2 = probably damaging, AlignGVGD = pathogenic (C65) -

CDKL5 disorder Pathogenic:1

Sep 06, 2024

Centre for Population Genomics, CPG

Significance: Likely 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 likely pathogenic. At least the following criteria are met: This variant is absent from gnomAD (PM2_Supporting). This variant has been identified as a de novo occurrence in an individual with CDKL5 disorder without confirmation of paternity and maternity (PM6, PMID: 17993579). Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). Well-established in vitro or in vivo functional studies supportive of a damaging effect on the protein function (PS3_supporting, PMID: 17993579). -

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

Aug 09, 2022

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. Experimental studies have shown that this missense change affects CDKL5 function (PMID: 17993579, 22922712, 29420175). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CDKL5 protein function. ClinVar contains an entry for this variant (Variation ID: 143830). This missense change has been observed in individual(s) with Rett syndrome (PMID: 17993579, 22670135; Invitae). 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 replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 220 of the CDKL5 protein (p.Leu220Pro). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.22	T;T;.;T;.;.
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.89	.;D;D;D;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Uncertain	-0.017	T
MutationAssessor	Pathogenic	3.0	M;.;.;M;.;M
PhyloP100		7.7
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-7.0	D;.;.;D;.;.
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D;.;.;D;.;.
Sift4G	Pathogenic	0.0	D;.;.;D;D;D
Polyphen		1.0	D;.;.;D;.;.
Vest4		0.96
MutPred		0.96		Loss of stability (P = 0.0028);Loss of stability (P = 0.0028);Loss of stability (P = 0.0028);Loss of stability (P = 0.0028);Loss of stability (P = 0.0028);Loss of stability (P = 0.0028);
MVP		0.97
MPC		3.4
ClinPred		1.0	D
GERP RS		6.1
Varity_R		1.0
gMVP		1.0
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs267608511; hg19: chrX-18606178;