X-18581942-G-T

Position:

• chrX-18581942-G-T

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.455G>T​(p.Cys152Phe) 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:4
• Conservation: PhyloP100: 10.0

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, 0.986
• PP5: Variant X-18581942-G-T is Pathogenic according to our data. Variant chrX-18581942-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11496.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18581942-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.455G>T	p.Cys152Phe	missense_variant	7/18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.455G>T	p.Cys152Phe	missense_variant	8/22		NP_001032420.1
CDKL5	NM_003159.3	c.455G>T	p.Cys152Phe	missense_variant	7/21		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.455G>T	p.Cys152Phe	missense_variant	7/18	1	NM_001323289.2	ENSP00000485244	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 2 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2004	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Nov 23, 2022	ACMG classification criteria: PS3 supporting, PS4 supporting, PM2 moderated, PM5 moderated, PM6 moderated, PP3 supporting -

CDKL5 disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

Centre for Population Genomics, CPG

Jul 17, 2024

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: Another missense variant in the same codon has been classified as pathogenic (PM5, ClinVar Variation ID: 658951). This variant has been identified as a de novo occurrence in an individual with CDKL5 disorder without confirmation of paternity and maternity (PM6, PMID: 15499549). At least one individual with this variant has been reported with a clinical phenotype consistent with CDKL5- related condition (PP4). This variant is absent from gnomAD (PM2_Supporting). -

Atypical Rett syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

curation

RettBASE

Mar 13, 2014

In vitro study (Ricciardi et al 2009) shows abnormal nuclear speckles; In silico prediction: SIFT = deleterious, MutationTaster = disease-causing, PolyPhen2 = probably damaging, AlignGVGD = benign (C0) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T;T;.;T;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;D;D;D;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.7	M;.;.;M;.;M
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-10	D;.;.;D;.;.
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D;.;.;D;.;.
Sift4G	Pathogenic	0.0	D;.;.;D;D;D
Polyphen		0.99	D;.;.;D;.;.
Vest4		0.90
MutPred		0.91		Gain of ubiquitination at K150 (P = 0.1008);Gain of ubiquitination at K150 (P = 0.1008);Gain of ubiquitination at K150 (P = 0.1008);Gain of ubiquitination at K150 (P = 0.1008);Gain of ubiquitination at K150 (P = 0.1008);Gain of ubiquitination at K150 (P = 0.1008);
MVP		0.97
MPC		3.2
ClinPred		1.0	D
GERP RS		6.1
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

LitVar

Other links and lift over

dbSNP: rs122460157; hg19: chrX-18600062;