rs267606713

chrX-18598499-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_001323289.2(CDKL5):c.863C>T(p.Thr288Ile) 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 (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T288R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: CDKL5 NM_001323289.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 7.38

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 9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 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-18598499-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1879751.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.919
• PP5: Variant X-18598499-C-T is Pathogenic according to our data. Variant chrX-18598499-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 11504.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKL5	NM_001323289.2	c.863C>T	p.Thr288Ile	missense_variant	11/18	ENST00000623535.2
CDKL5	NM_001037343.2	c.863C>T	p.Thr288Ile	missense_variant	12/22
CDKL5	NM_003159.3	c.863C>T	p.Thr288Ile	missense_variant	11/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKL5	ENST00000623535.2	c.863C>T	p.Thr288Ile	missense_variant	11/18	1	NM_001323289.2	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Developmental and epileptic encephalopathy, 2 Pathogenic:2

Pathogenic, no assertion criteria provided	curation	RettBASE	Mar 13, 2014	Highly conserved residue, not found in healthy mother of affected son; In silico prediction: SIFT = deleterious, MutationTaster = disease-causing, PolyPhen2 = possibly damaging, AlignGVGD = benign (C0) -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 23, 2008	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.079	T;T;.;T;.;.
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	-0.040	N;.;.;N;.;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.6	N;.;.;N;.;.
REVEL	Uncertain	0.48
Sift	Uncertain	0.013	D;.;.;D;.;.
Sift4G	Benign	0.36	T;.;.;T;T;T
Polyphen		0.78	P;.;.;P;.;.
Vest4		0.94
MutPred		0.89		Loss of phosphorylation at T288 (P = 0.0506);Loss of phosphorylation at T288 (P = 0.0506);Loss of phosphorylation at T288 (P = 0.0506);Loss of phosphorylation at T288 (P = 0.0506);Loss of phosphorylation at T288 (P = 0.0506);Loss of phosphorylation at T288 (P = 0.0506);
MVP		0.96
MPC		0.62
ClinPred		0.74	D
GERP RS		5.5
Varity_R		0.80
gMVP		0.82

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: rs267606713; hg19: chrX-18616619;