chrX-18604816-T-C

Position:

chrX-18604816-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BS2BA1BP2

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Ile631Thr variant in CDKL5 is 0.03% in African sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Ile631Thr variant is observed in at least 2 unaffected individuals (internal database) (BS2). The p.Ile631Thr variant is observed in the CDKL5 gene where a second pathogenic variant in the same gene is present in the patient (PMID 19793311) (BP2). In summary, the p.Ile631Thr variant in CDKL5 is classified as benign based on the ACMG/AMP criteria (BA1, BS2, BP2). LINK:https://erepo.genome.network/evrepo/ui/classification/CA170457/MONDO:0100039/016

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., 3 hem., cov: 23)

Exomes 𝑓: 0.000016 ( 0 hom. 5 hem. )

Consequence

CDKL5
NM_001323289.2 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:4B:4

Conservation

PhyloP100: 5.59

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 -13 ACMG points.

BP2

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

BS2

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

BA1

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.1892T>C	p.Ile631Thr	missense_variant	12/18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2 linkuse as main transcript	c.1892T>C	p.Ile631Thr	missense_variant	13/22		NP_001032420.1
CDKL5	NM_003159.3 linkuse as main transcript	c.1892T>C	p.Ile631Thr	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.1892T>C	p.Ile631Thr	missense_variant	12/18	1	NM_001323289.2	ENSP00000485244	P1	O76039-2

Frequencies

GnomAD3 genomes

AF:

0.000108

AC:

AN:

111619

Hom.:

Cov.:

AF XY:

0.0000887

AC XY:

AN XY:

33825

show subpopulations

Gnomad AFR

AF:

0.000392

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000328

AC:

AN:

182969

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67535

show subpopulations

Gnomad AFR exome

AF:

0.000304

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000144

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1098002

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

363358

show subpopulations

Gnomad4 AFR exome

AF:

0.000530

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000662

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.000108

AC:

AN:

111619

Hom.:

Cov.:

AF XY:

0.0000887

AC XY:

AN XY:

33825

show subpopulations

Gnomad4 AFR

AF:

0.000392

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000475

Hom.:

Bravo

AF:

0.000144

ESP6500AA

AF:

0.000782

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Benign

Submissions summary: Uncertain:4Benign: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	Apr 13, 2020	This variant is associated with the following publications: (PMID: 19793311) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 09, 2015	- -

CDKL5 disorder

Benign:2

Benign, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Sep 13, 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). -
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.Ile631Thr variant in CDKL5 is 0.03% in African sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Ile631Thr variant is observed in at least 2 unaffected individuals (internal database) (BS2). The p.Ile631Thr variant is observed in the CDKL5 gene where a second pathogenic variant in the same gene is present in the patient (PMID 19793311) (BP2). In summary, the p.Ile631Thr variant in CDKL5 is classified as benign based on the ACMG/AMP criteria (BA1, BS2, BP2). -

Developmental and epileptic encephalopathy, 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Nov 01, 2016

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2017

The p.I631T variant (also known as c.1892T>C), located in coding exon 11 of the CDKL5 gene, results from a T to C substitution at nucleotide position 1892. The isoleucine at codon 631 is replaced by threonine, an amino acid with similar properties. This alteration was detected as maternally inherited in an individual with early onset seizures (Nemos C et al. Clin. Genet., 2009 Oct;76:357-71). This amino acid position is not 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. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 19, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 631 of the CDKL5 protein (p.Ile631Thr). This variant is present in population databases (rs144878564, gnomAD 0.02%). This missense change has been observed in individual(s) with seizures (PMID: 19793311). ClinVar contains an entry for this variant (Variation ID: 143786). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CDKL5 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Benign:1

Likely benign, no assertion criteria provided

curation

RettBASE

May 09, 2014

Identified in unaffect female with random X-inactivation pattern; in silico predictions: SIFT = tolerated, MutationTaster = polymorphism, PolyPhen2 = benign, AlignGVGD = benign (C0) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.70

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.030

T;T;T;.;.

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.81

.;T;T;T;T

M_CAP

Benign

0.078

MetaRNN

Benign

0.059

T;T;T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.1

L;.;L;.;L

MutationTaster

Benign

0.98

N;N

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.81

N;.;N;.;.

REVEL

Benign

0.13

Sift

Uncertain

0.0040

D;.;D;.;.

Sift4G

Benign

0.13

T;.;T;T;T

Polyphen

0.0

B;.;B;.;.

Vest4

0.35

MVP

0.44

MPC

0.44

ClinPred

0.069

GERP RS

4.7

Varity_R

0.14

gMVP

0.17

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