X-18507154-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_001323289.2(CDKL5):c.58G>C(p.Gly20Arg) 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. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G20V) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: CDKL5 NM_001323289.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• 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 12 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001323289.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-18507155-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 918032.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant X-18507154-G-C is Pathogenic according to our data. Variant chrX-18507154-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 143828.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKL5	NM_001323289.2	c.58G>C	p.Gly20Arg	missense_variant	2/18	ENST00000623535.2
CDKL5	NM_001037343.2	c.58G>C	p.Gly20Arg	missense_variant	3/22
CDKL5	NM_003159.3	c.58G>C	p.Gly20Arg	missense_variant	2/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKL5	ENST00000623535.2	c.58G>C	p.Gly20Arg	missense_variant	2/18	1	NM_001323289.2	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 2 Pathogenic:1

Likely pathogenic, no assertion criteria provided

curation

RettBASE

Mar 13, 2014

In silico prediction: SIFT = deleterious, MutationTaster = disease-causing, PolyPhen2 = probably damaging, AlignGVGD = benign (C0) -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 19, 2022

For these reasons, this variant has been classified as Pathogenic. 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: 143828). This missense change has been observed in individual(s) with CDKL5-related conditions (PMID: 20397747, 30776697). 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 glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 20 of the CDKL5 protein (p.Gly20Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.22	T;T;.;T;.;.;.;.
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	3.9	H;.;.;H;.;.;.;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.3	D;.;.;D;.;.;.;.
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;.;.;D;.;.;.;.
Sift4G	Uncertain	0.0030	D;.;.;D;D;D;D;D
Polyphen		1.0	D;.;.;D;.;.;.;.
Vest4		0.96
MutPred		0.95		Gain of MoRF binding (P = 0.0565);Gain of MoRF binding (P = 0.0565);Gain of MoRF binding (P = 0.0565);Gain of MoRF binding (P = 0.0565);Gain of MoRF binding (P = 0.0565);Gain of MoRF binding (P = 0.0565);Gain of MoRF binding (P = 0.0565);Gain of MoRF binding (P = 0.0565);
MVP		0.99
MPC		2.8
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.99
gMVP		0.97

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: rs267608418; hg19: chrX-18525274;