rs201893287

Positions:

chrX-18604447-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BS2BP4BS1

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Ile508Thr variant in CDKL5 is 0.018% in European (Non-Finnish) sub population in gnomAD, which is high enough to be classified as likely benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Ile508Thr variant is observed in at least 2 unaffected individuals (internal database) (BS2). Computational analysis prediction tools suggest that the p.Ile508Thr variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Ile508Thr variant in CDKL5 is classified as benign based on the ACMG/AMP criteria (BS1, BS2, BP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA170449/MONDO:0100039/016

Frequency

Genomes: 𝑓 0.000081 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.00017 ( 0 hom. 51 hem. )

Consequence

CDKL5
NM_001323289.2 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:6

Conservation

PhyloP100: 3.01

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

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

BS1

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
CDKL5	NM_001323289.2 linkuse as main transcript	c.1523T>C	p.Ile508Thr	missense_variant	12/18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2 linkuse as main transcript	c.1523T>C	p.Ile508Thr	missense_variant	13/22		NP_001032420.1
CDKL5	NM_003159.3 linkuse as main transcript	c.1523T>C	p.Ile508Thr	missense_variant	12/21		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2 linkuse as main transcript	c.1523T>C	p.Ile508Thr	missense_variant	12/18	1	NM_001323289.2	ENSP00000485244	P1	O76039-2

Frequencies

GnomAD3 genomes

AF:

0.0000805

AC:

AN:

111746

Hom.:

Cov.:

AF XY:

0.0000295

AC XY:

AN XY:

33918

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000947

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:

0.000151

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000109

AC:

AN:

183248

Hom.:

AF XY:

0.0000591

AC XY:

AN XY:

67728

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000729

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000524

Gnomad FIN exome

AF:

0.0000625

Gnomad NFE exome

AF:

0.000184

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.000174

AC:

191

AN:

1097997

Hom.:

Cov.:

AF XY:

0.000140

AC XY:

AN XY:

363353

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000114

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000369

Gnomad4 FIN exome

AF:

0.0000493

Gnomad4 NFE exome

AF:

0.000209

Gnomad4 OTH exome

AF:

0.000152

GnomAD4 genome

AF:

0.0000805

AC:

AN:

111746

Hom.:

Cov.:

AF XY:

0.0000295

AC XY:

AN XY:

33918

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000947

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000151

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000197

Hom.:

Bravo

AF:

0.0000604

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000692

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

CDKL5 disorder

Benign:2

Benign, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Aug 25, 2022	The allele frequency of the p.Ile508Thr variant in CDKL5 is 0.018% in European (Non-Finnish) sub population in gnomAD, which is high enough to be classified as likely benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Ile508Thr variant is observed in at least 2 unaffected individuals (internal database) (BS2). Computational analysis prediction tools suggest that the p.Ile508Thr variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Ile508Thr variant in CDKL5 is classified as benign based on the ACMG/AMP criteria (BS1, BS2, BP4). -
Benign, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Jul 12, 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 benign. At least the following criteria are met: The allele frequency of this variant in at least one population in gnomAD is higher than the 0.03% threshold defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders VCEP 3.0 (BA1). -

Autism

Uncertain:1

Uncertain significance, no assertion criteria provided

curation

RettBASE

May 09, 2014

In silico predictions: SIFT = deleterious, MutationTaster = polymorphism, PolyPhen2 = benign, AlignGVGD = benign (C0) -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 13, 2020

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 04, 2018

- -

CDKL5-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 31, 2023

This variant is classified as 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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Benign

0.76

DEOGEN2

Benign

0.026

T;T;T;.;.

FATHMM_MKL

Benign

0.70

LIST_S2

Uncertain

0.90

.;D;D;D;D

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.098

T;T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.4

L;.;L;.;L

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.45

N;.;N;.;.

REVEL

Benign

0.10

Sift

Uncertain

0.0070

D;.;D;.;.

Sift4G

Benign

0.40

T;.;T;T;T

Polyphen

0.090

B;.;B;.;.

Vest4

0.34

MVP

0.59

MPC

0.44

ClinPred

0.14

GERP RS

6.1

Varity_R

0.074

gMVP

0.079

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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