rs267608500

Positions:

• chrX-18587977-A-C
• chrX-18587977-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_001323289.2(CDKL5):​c.578A>C​(p.Asp193Ala) 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: CDKL5 NM_001323289.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.95

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant X-18587977-A-C is Pathogenic according to our data. Variant chrX-18587977-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 1432338.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.578A>C	p.Asp193Ala	missense_variant	9/18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.578A>C	p.Asp193Ala	missense_variant	10/22		NP_001032420.1
CDKL5	NM_003159.3	c.578A>C	p.Asp193Ala	missense_variant	9/21		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.578A>C	p.Asp193Ala	missense_variant	9/18	1	NM_001323289.2	ENSP00000485244	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 27, 2021

This sequence change replaces aspartic acid with alanine at codon 193 of the CDKL5 protein (p.Asp193Ala). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and alanine. This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp193 amino acid residue in CDKL5. Other variant(s) that disrupt this residue have been observed in individuals with CDKL5-related conditions (PMID: 23583054, 30898514), which suggests that this may be a clinically significant amino acid residue. 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. This missense change has been observed in individual(s) with clinical features of CDKL5-related conditions (Invitae). In at least one individual the variant was observed to be de novo. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T;T;.;T;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	.;D;D;D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	4.0	H;.;.;H;.;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-8.0	D;.;.;D;.;.
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D;.;.;D;.;.
Sift4G	Pathogenic	0.0010	D;.;.;D;D;D
Polyphen		1.0	D;.;.;D;.;.
Vest4		0.99
MutPred		0.95		Loss of ubiquitination at K190 (P = 0.1151);Loss of ubiquitination at K190 (P = 0.1151);Loss of ubiquitination at K190 (P = 0.1151);Loss of ubiquitination at K190 (P = 0.1151);Loss of ubiquitination at K190 (P = 0.1151);Loss of ubiquitination at K190 (P = 0.1151);
MVP		0.98
MPC		2.8
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.99
gMVP		1.0

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-18606097;