X-18625216-G-A

Position:

chrX-18625216-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

This summary comes from the ClinGen Evidence Repository: The p.Arg822His variant in CDKL5 is present in 3 XX and 1 XY individuals in gnomAD v3.1.2 (0.0076%) (not sufficient to meet BS1 criteria). Computational analysis prediction tools suggest that the p.Arg822His variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). The p.Arg822His variant is observed in at least 2 unaffected individuals (internal database-GeneDX) (BS2). In summary, the p.Arg822His variant in CDKL5 is classified as Likely Benign based on the ACMG/AMP criteria (BS2, BP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10360541/MONDO:0100039/016

Frequency

Genomes: 𝑓 0.000037 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.000013 ( 0 hom. 8 hem. )

Consequence

CDKL5
NM_001323289.2 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:3B:4

Conservation

PhyloP100: 4.83

Variant links:

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]

CDKL5 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BS2

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKL5	NM_001323289.2 linkuse as main transcript	c.2465G>A	p.Arg822His	missense_variant	17/18	ENST00000623535.2	NP_001310218.1	O76039-2
CDKL5	NM_001037343.2 linkuse as main transcript	c.2465G>A	p.Arg822His	missense_variant	18/22		NP_001032420.1	O76039-1
CDKL5	NM_003159.3 linkuse as main transcript	c.2465G>A	p.Arg822His	missense_variant	17/21		NP_003150.1	O76039-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2 linkuse as main transcript	c.2465G>A	p.Arg822His	missense_variant	17/18	1	NM_001323289.2	ENSP00000485244.1		O76039-2

Frequencies

GnomAD3 genomes

AF:

0.0000366

AC:

AN:

109345

Hom.:

Cov.:

AF XY:

0.0000316

AC XY:

AN XY:

31649

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000761

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000548

AC:

AN:

182596

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67176

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000128

AC:

AN:

1095860

Hom.:

Cov.:

AF XY:

0.0000221

AC XY:

AN XY:

361488

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000167

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000366

AC:

AN:

109345

Hom.:

Cov.:

AF XY:

0.0000316

AC XY:

AN XY:

31649

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000761

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000416

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:3Benign:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 07, 2021	See Variant Classification Assertion Criteria. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 30, 2016	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 04, 2016

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 30, 2019

The p.R822H variant (also known as c.2465G>A), located in coding exon 16 of the CDKL5 gene, results from a G to A substitution at nucleotide position 2465. The arginine at codon 822 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

CDKL5 disorder

Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Feb 20, 2023

The p.Arg822His variant in CDKL5 is present in 3 XX and 1 XY individuals in gnomAD v3.1.2 (0.0076%) (not sufficient to meet BS1 criteria). Computational analysis prediction tools suggest that the p.Arg822His variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). The p.Arg822His variant is observed in at least 2 unaffected individuals (internal database-GeneDX) (BS2). In summary, the p.Arg822His variant in CDKL5 is classified as Likely Benign based on the ACMG/AMP criteria (BS2, BP4). -

CDKL5-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 02, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 06, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.032

T;T;T;.

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.90

.;D;D;D

M_CAP

Pathogenic

0.52

MetaRNN

Benign

0.20

T;T;T;T

MetaSVM

Benign

-0.77

MutationAssessor

Benign

0.26

N;.;N;N

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.30

N;.;N;.

REVEL

Benign

0.12

Sift

Benign

0.17

T;.;T;.

Sift4G

Benign

0.16

T;.;T;T

Polyphen

0.066

B;.;B;.

Vest4

0.13

MVP

0.66

MPC

0.43

ClinPred

0.23

GERP RS

6.0

Varity_R

0.090

gMVP

0.12

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over