rs376341076

Variant names:

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 highest population minor allele frequency of the c.1684A>G (p.Thr562Ala) variant in CDKL5 in gnomAD v4.1 is 0.000004 in the European (Non-Finnish) population (not sufficient to meet BS1 criteria). The computational predictor REVEL gives a score of 0.133, evidence that does not predict a damaging effect on CDKL5 function (BP4). The p.Thr562Ala variant is observed in at least 2 unaffected individuals (Ambry Genetics: internal database, Labcorp Genetics Inc. (formerly Invitae): internal database) (BS2). In summary, the p.Thr562Ala variant in CDKL5 is classified as Likely Benign for CDKL5-associated disorder based on the ACMG/AMP criteria (BP4, BS2) (CDKL5 Specifications v.3.0; curation approved on 02/28/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10360405/MONDO:0100039/034

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000027 ( 0 hom. 1 hem. )

Consequence

CDKL5
NM_001323289.2 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:2B:3

Conservation

PhyloP100: 1.01

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 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 rank	MANE	Protein	UniProt
CDKL5	NM_001323289.2 link	c.1684A>G	p.Thr562Ala	missense_variant	Exon 12 of 18	ENST00000623535.2	NP_001310218.1	O76039-2
CDKL5	NM_001037343.2 link	c.1684A>G	p.Thr562Ala	missense_variant	Exon 13 of 22		NP_001032420.1	O76039-1
CDKL5	NM_003159.3 link	c.1684A>G	p.Thr562Ala	missense_variant	Exon 12 of 21		NP_003150.1	O76039-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2 link	c.1684A>G	p.Thr562Ala	missense_variant	Exon 12 of 18	1	NM_001323289.2	ENSP00000485244.1		O76039-2

Frequencies

GnomAD3 genomes

AF:

0.00000891

AC:

AN:

112279

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34443

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000273

AC:

AN:

1098214

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363570

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:

0.00000356

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000891

AC:

AN:

112279

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34443

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:

0.0000188

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2Benign:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

CDKL5 disorder

Benign:2

Feb 28, 2025

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

The highest population minor allele frequency of the c.1684A>G (p.Thr562Ala) variant in CDKL5 in gnomAD v4.1 is 0.000004 in the European (Non-Finnish) population (not sufficient to meet BS1 criteria). The computational predictor REVEL gives a score of 0.133, evidence that does not predict a damaging effect on CDKL5 function (BP4). The p.Thr562Ala variant is observed in at least 2 unaffected individuals (Ambry Genetics: internal database, Labcorp Genetics Inc. (formerly Invitae): internal database) (BS2). In summary, the p.Thr562Ala variant in CDKL5 is classified as Likely Benign for CDKL5-associated disorder based on the ACMG/AMP criteria (BP4, BS2) (CDKL5 Specifications v.3.0; curation approved on 02/28/2025). -

Jul 12, 2024

Centre for Population Genomics, CPG

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

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 likely benign. At least the following criteria are met: The variant is observed in at least 2 individuals with no features of CDKL5 disorder (BS2). ClinVar Variation ID: 434666 There are 4 individuals in gnomAD v4 (1 hemizygote), AF <0.008% Computational prediction analysis tools suggest no impact on gene product (REVEL score <= 0.15) (BP4). -

not specified

Uncertain:1

Aug 16, 2016

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Uncertain:1

May 02, 2016

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T562A variant (also known as c.1684A>G), located in coding exon 11 of the CDKL5 gene, results from an A to G substitution at nucleotide position 1684. The threonine at codon 562 is replaced by alanine, an amino acid with similar properties. This variant was previously reported in the SNPDatabase as rs376341076. Based on data from the NHLBI Exome Sequencing Project (ESP), the G allele was absent out of 2443 total male alleles studied. 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

Benign:1

Dec 09, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.75

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.023

T;T;T;.;.

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.74

.;T;T;T;T

M_CAP

Benign

0.051

MetaRNN

Benign

0.12

T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.41

N;.;N;.;N

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.71

N;.;N;.;.

REVEL

Benign

0.13

Sift

Uncertain

0.010

D;.;D;.;.

Sift4G

Benign

0.49

T;.;T;T;T

Polyphen

0.0010

B;.;B;.;.

Vest4

0.10

MVP

0.63

MPC

0.34

ClinPred

0.10

GERP RS

-0.88

Varity_R

0.093

gMVP

0.34

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