chrX-18575399-T-C

Position:

• chrX-18575399-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001323289.2(CDKL5):​c.191T>C​(p.Leu64Pro) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: CDKL5 NM_001323289.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 8.02

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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.191T>C	p.Leu64Pro	missense_variant	5/18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.191T>C	p.Leu64Pro	missense_variant	6/22		NP_001032420.1
CDKL5	NM_003159.3	c.191T>C	p.Leu64Pro	missense_variant	5/21		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.191T>C	p.Leu64Pro	missense_variant	5/18	1	NM_001323289.2	ENSP00000485244	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

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 = pathogenic (C65) -

CDKL5 disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Centre for Population Genomics, CPG

Sep 24, 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 a variant of uncertain significance. At least the following criteria are met: Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). This variant is absent from gnomAD (PM2_Supporting). This variant has been identified as a de novo occurrence in an individual with CDKL5 disorder without confirmation of maternity (PM6). PMID: 19564592 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.28	T;T;.;T;.;.;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	.;T;T;T;T;T;T
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Pathogenic	4.0	H;.;.;H;.;.;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-7.0	D;.;.;D;.;.;.
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D;.;.;D;.;.;.
Sift4G	Pathogenic	0.0	D;.;.;D;D;D;D
Polyphen		1.0	D;.;.;D;.;.;.
Vest4		1.0
MutPred		0.89		Loss of stability (P = 0.0125);Loss of stability (P = 0.0125);Loss of stability (P = 0.0125);Loss of stability (P = 0.0125);Loss of stability (P = 0.0125);Loss of stability (P = 0.0125);Loss of stability (P = 0.0125);
MVP		0.98
MPC		3.4
ClinPred		1.0	D
GERP RS		5.7
Varity_R		1.0
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: rs267608435; hg19: chrX-18593519;