X-18507155-G-A

Variant names:

• chrX-18507155-G-A
• rs786204962
• NM_001323289.2:c.59G>A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001323289.2(CDKL5):​c.59G>A​(p.Gly20Asp) 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. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: CDKL5 NM_001323289.2 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.37

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant X-18507155-G-A is Pathogenic according to our data. Variant chrX-18507155-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189548.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18507155-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.59G>A	p.Gly20Asp	missense_variant	Exon 2 of 18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.59G>A	p.Gly20Asp	missense_variant	Exon 3 of 22		NP_001032420.1
CDKL5	NM_003159.3	c.59G>A	p.Gly20Asp	missense_variant	Exon 2 of 21		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.59G>A	p.Gly20Asp	missense_variant	Exon 2 of 18	1	NM_001323289.2	ENSP00000485244.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CDKL5 disorder Pathogenic:1

Jul 04, 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: Occurs in the well-characterized ATP binding region of CDKL5 (PM1). Another missense variant in the same codon has been classified as pathogenic (PM5, ClinVar Variation ID: 918032). Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). This variant is absent from gnomAD (PM2_Supporting). -

not provided Pathogenic:1

Mar 13, 2014

RettBASE

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

Conserved amino acid in the catalytic domain -

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

Feb 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 20 of the CDKL5 protein (p.Gly20Asp). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Gly20 amino acid residue in CDKL5. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20397747, 29420175). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects CDKL5 function (PMID: 30266825). 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: 189548). This variant has not been reported in the literature in individuals affected with CDKL5-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;T;.;T;.;.;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	.;T;T;T;D;D;T;T
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Pathogenic	3.2	M;.;.;M;.;.;.;M
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-5.5	D;.;.;D;.;.;.;.
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;.;.;D;.;.;.;.
Sift4G	Uncertain	0.0030	D;.;.;D;D;D;D;D
Polyphen		1.0	D;.;.;D;.;.;.;.
Vest4		0.95
MutPred		0.92		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		1.0
MPC		3.0
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.98
gMVP		0.98

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

Publications

LitVar

Other links and lift over

dbSNP: rs786204962; hg19: chrX-18525275;