rs267608611

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS2BP4

This summary comes from the ClinGen Evidence Repository: The p.Asn399Thr variant in CDKL5 is observed in at least 2 unaffected individuals (internal database) (BS2). This variant is also present in the heterozygous state in two individuals in gnomAD. Computational analysis prediction tools suggest that the p.Asn399Thr variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Asn399Thr variant in CDKL5 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA170438/MONDO:0100039/016

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000013 ( 0 hom. 3 hem. )

Consequence

CDKL5
NM_001323289.2 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:4B:2

Conservation

PhyloP100: 4.04

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

CDKL5 disorder
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
developmental and epileptic encephalopathy, 2
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
atypical Rett syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
genetic developmental and epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
infantile spasms
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
precocious puberty
Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

CDKL5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001323289.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CDKL5	NM_001323289.2	MANE Select	c.1196A>C	p.Asn399Thr	missense	Exon 12 of 18	NP_001310218.1
CDKL5	NM_001037343.2		c.1196A>C	p.Asn399Thr	missense	Exon 13 of 22	NP_001032420.1
CDKL5	NM_003159.3		c.1196A>C	p.Asn399Thr	missense	Exon 12 of 21	NP_003150.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CDKL5	ENST00000623535.2	TSL:1 MANE Select	c.1196A>C	p.Asn399Thr	missense	Exon 12 of 18	ENSP00000485244.1
CDKL5	ENST00000379989.6	TSL:1	c.1196A>C	p.Asn399Thr	missense	Exon 13 of 22	ENSP00000369325.3
CDKL5	ENST00000379996.7	TSL:1	c.1196A>C	p.Asn399Thr	missense	Exon 12 of 21	ENSP00000369332.3

Frequencies

GnomAD3 genomes

AF:

0.00000895

AC:

AN:

111693

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.0000109

AC:

AN:

183174

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000245

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000127

AC:

AN:

1098105

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

363469

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26400

American (AMR)

AF:

0.00

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19385

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.00

AC:

AN:

54144

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40522

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.0000154

AC:

AN:

842013

Other (OTH)

AF:

0.0000217

AC:

AN:

46091

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000895

AC:

AN:

111693

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33863

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30673

American (AMR)

AF:

0.00

AC:

AN:

10493

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2651

East Asian (EAS)

AF:

0.00

AC:

AN:

3567

South Asian (SAS)

AF:

0.00

AC:

AN:

2667

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6021

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53190

Other (OTH)

AF:

0.00

AC:

AN:

1507

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000272

Hom.:

Bravo

AF:

0.00000756

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Benign

Submissions summary: Uncertain:4Benign:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

CDKL5 disorder

Benign:2

Aug 27, 2025

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The highest population minor allele frequency of the p.Asn399Thr variant in CDKL5 in gnomAD v4.1 is 0.0000156 in Non-Finnish European population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (=0.0000083) for BS1, and therefore meets this criterion (BS1). The p.Asn399Thr variant in CDKL5 is observed in at least 2 unaffected individuals (internal database - GeneDx) (BS2). Computational analysis prediction tools suggest that the p.Asn399Thr variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Asn399Thr variant in CDKL5 is classified as benign based on the ACMG/AMP criteria (BS1, BS2, BP4). (CDKL5 Specifications v.5.0.0; curation approved on 8/27/2025)

Sep 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, ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel internal database). Computational prediction analysis tools suggest no impact on gene product (REVEL score <= 0.15) (BP4).

not specified

Uncertain:1

Feb 21, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CDKL5 c.1196A>C (p.Asn399Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.1e-05 in 183174 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1196A>C has been reported in the literature in at-least one individual affected with Neurodevelopmental phenotypes including infantile spasms, severe psychomotor delay, renal failure, and abnormal EGG and brain MRI (Sprovieri_2009). These report(s) do not provide unequivocal conclusions about association of the variant with Early Infantile Epileptic Encephalopathy 2. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 19253388). ClinVar contains an entry for this variant (Variation ID: 143770). Based on the evidence outlined above, the variant was classified as uncertain significance.

Developmental and epileptic encephalopathy, 2

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Uncertain:1

Jan 07, 2016

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The N399T variant in the CDKL5 gene has been reported previously in a female with Rett syndrome, whose mother did not carry the variant and her father was unavailable for testing (Sprovieri et al., 2009). The N399T variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The N399T variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Asparagine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret N399T as a variant of uncertain significance

Atypical Rett syndrome

Uncertain:1

Mar 13, 2014

RettBASE

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:curation

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.053

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.19

MetaSVM

Benign

-0.78

MutationAssessor

Benign

1.9

PhyloP100

4.0

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-2.0

REVEL

Benign

0.15

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.056

Polyphen

0.13

Vest4

0.54

MVP

0.86

MPC

0.62

ClinPred

0.43

GERP RS

4.9

Varity_R

0.47

gMVP

0.21

Mutation Taster

=74/26

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over