Variant rs148697943 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BA1BP7BS2_Supporting

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Glu60= variant in CDKL5 is 0.9% in East Asian 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.Glu60= variant is observed in at least 1 unaffected individual (internal database) (BS2_supporting). The silent p.Glu60= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). In summary, the p.Glu60= variant in CDKL5 is classified as benign based on the ACMG/AMP criteria (BA1, BS2_supporting, BP7). LINK:https://erepo.genome.network/evrepo/ui/classification/CA200253/MONDO:0100039/016

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., 19 hem., cov: 23)

Exomes 𝑓: 0.00017 ( 0 hom. 75 hem. )

Consequence

CDKL5
NM_001323289.2 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:6

Conservation

PhyloP100: 5.93

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 Benign. Variant got -10 ACMG points.

BP7

BS2

BA1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CDKL5	NM_001323289.2 linkuse as main transcript	c.180G>A	p.Glu60=	synonymous_variant	5/18	ENST00000623535.2
CDKL5	NM_001037343.2 linkuse as main transcript	c.180G>A	p.Glu60=	synonymous_variant	6/22
CDKL5	NM_003159.3 linkuse as main transcript	c.180G>A	p.Glu60=	synonymous_variant	5/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKL5	ENST00000623535.2 linkuse as main transcript	c.180G>A	p.Glu60=	synonymous_variant	5/18	1	NM_001323289.2	P1	O76039-2

Frequencies

GnomAD3 genomes

AF:

0.000259

AC:

AN:

111992

Hom.:

Cov.:

AF XY:

0.000527

AC XY:

AN XY:

34172

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:

0.00759

Gnomad SAS

AF:

0.000372

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000722

AC:

132

AN:

182939

Hom.:

AF XY:

0.000873

AC XY:

AN XY:

67605

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00904

Gnomad SAS exome

AF:

0.000315

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000222

GnomAD4 exome

AF:

0.000170

AC:

186

AN:

1094703

Hom.:

Cov.:

AF XY:

0.000208

AC XY:

AN XY:

360331

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00451

Gnomad4 SAS exome

AF:

0.000499

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000479

GnomAD4 genome

AF:

0.000259

AC:

AN:

112047

Hom.:

Cov.:

AF XY:

0.000555

AC XY:

AN XY:

34237

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00761

Gnomad4 SAS

AF:

0.000373

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000291

Hom.:

Bravo

AF:

0.000438

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 10, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 10, 2015	- -

CDKL5 disorder

Benign:1

Benign, reviewed by expert panel

curation

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Mar 26, 2021

The allele frequency of the p.Glu60= variant in CDKL5 is 0.9% in East Asian 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.Glu60= variant is observed in at least 1 unaffected individual (internal database) (BS2_supporting). The silent p.Glu60= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). In summary, the p.Glu60= variant in CDKL5 is classified as benign based on the ACMG/AMP criteria (BA1, BS2_supporting, BP7). -

CDKL5-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 26, 2019

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

Invitae

Dec 28, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.39

CADD

Benign

9.5

DANN

Benign

0.63

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