chrX-18604120-A-C

Variant names:

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	UniProt
CDKL5	NM_001323289.2	MANE Select	c.1196A>C	p.Asn399Thr	missense	Exon 12 of 18	NP_001310218.1	O76039-2
CDKL5	NM_001037343.2		c.1196A>C	p.Asn399Thr	missense	Exon 13 of 22	NP_001032420.1	O76039-1
CDKL5	NM_003159.3		c.1196A>C	p.Asn399Thr	missense	Exon 12 of 21	NP_003150.1	O76039-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDKL5	ENST00000623535.2	TSL:1 MANE Select	c.1196A>C	p.Asn399Thr	missense	Exon 12 of 18	ENSP00000485244.1	O76039-2
CDKL5	ENST00000379989.6	TSL:1	c.1196A>C	p.Asn399Thr	missense	Exon 13 of 22	ENSP00000369325.3	O76039-1
CDKL5	ENST00000379996.7	TSL:1	c.1196A>C	p.Asn399Thr	missense	Exon 12 of 21	ENSP00000369332.3	O76039-1

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

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

CDKL5 disorder (2)

Atypical Rett syndrome (1)

Developmental and epileptic encephalopathy, 2 (1)

not provided (1)

not specified (1)

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

Computational scores

Splicing

Publications

Other links and lift over