rs267606714

chrX-18598508-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_001323289.2(CDKL5):c.872G>A(p.Cys291Tyr) 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 Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C291R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: CDKL5 NM_001323289.2 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:3
• Conservation: PhyloP100: 9.36

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 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 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-18598507-T-C is described in ClinVar as [Uncertain_significance]. Clinvar id is 429431.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKL5	NM_001323289.2	c.872G>A	p.Cys291Tyr	missense_variant	11/18	ENST00000623535.2
CDKL5	NM_001037343.2	c.872G>A	p.Cys291Tyr	missense_variant	12/22
CDKL5	NM_003159.3	c.872G>A	p.Cys291Tyr	missense_variant	11/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKL5	ENST00000623535.2	c.872G>A	p.Cys291Tyr	missense_variant	11/18	1	NM_001323289.2	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:3

Revision: reviewed by expert panel

Submissions by phenotype

Developmental and epileptic encephalopathy, 2 Pathogenic:1 Uncertain:1

Uncertain significance, no assertion criteria provided	curation	RettBASE	Mar 13, 2014	Conserved residue; In silico prediction: SIFT = deleterious, MutationTaster = disease-causing, PolyPhen2 = probably damaging, AlignGVGD = benign (C0) -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 23, 2008	- -

CDKL5 disorder Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Aug 25, 2022

The p.Cys291Tyr variant in CDKL5 has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with severe early-onset encephalopathy (PMID 18809835) (PM6). The p.Cys291Tyr variant in CDKL5 is absent from gnomAD (PM2_Supporting). The p.Cys291Tyr variant has been observed in at least 1 other individual with CDKL5-related disorder (PMID 18809835, PMID 25657822) (PS4_Supporting). In summary, the p.Cys291Tyr variant in CDKL5 is classified as a variant of unknown significance based on the ACMG/AMP criteria (PM6, PM2_Supporting, PS4_Supporting). -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 15, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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: 11505). This missense change has been observed in individual(s) with clinical features of CDKL5-related disorder (PMID: 18809835, 25657822). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 291 of the CDKL5 protein (p.Cys291Tyr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.21	T;T;.;T;.;.
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.6	L;.;.;L;.;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-6.1	D;.;.;D;.;.
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0010	D;.;.;D;.;.
Sift4G	Uncertain	0.030	D;.;.;D;D;D
Polyphen		1.0	D;.;.;D;.;.
Vest4		0.86
MutPred		0.87		Gain of phosphorylation at C291 (P = 0.0469);Gain of phosphorylation at C291 (P = 0.0469);Gain of phosphorylation at C291 (P = 0.0469);Gain of phosphorylation at C291 (P = 0.0469);Gain of phosphorylation at C291 (P = 0.0469);Gain of phosphorylation at C291 (P = 0.0469);
MVP		0.93
MPC		1.2
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.99
gMVP		0.93

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: rs267606714; hg19: chrX-18616628;