rs267608429

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The NM_001323289.2(CDKL5):c.125A>G(p.Lys42Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 21)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

CDKL5
NM_001323289.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 4.01

Publications

15 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: Pathogenic. The variant received 14 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001323289.2

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.905

PP5

Variant X-18564502-A-G is Pathogenic according to our data. Variant chrX-18564502-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 143772.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKL5	NM_001323289.2 link	c.125A>G	p.Lys42Arg	missense_variant	Exon 4 of 18	ENST00000623535.2	NP_001310218.1	O76039-2
CDKL5	NM_001037343.2 link	c.125A>G	p.Lys42Arg	missense_variant	Exon 5 of 22		NP_001032420.1	O76039-1
CDKL5	NM_003159.3 link	c.125A>G	p.Lys42Arg	missense_variant	Exon 4 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.125A>G	p.Lys42Arg	missense_variant	Exon 4 of 18	1	NM_001323289.2	ENSP00000485244.1		O76039-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

987881

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

279289

African (AFR)

AF:

0.00

AC:

AN:

24394

American (AMR)

AF:

0.00

AC:

AN:

34731

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18187

East Asian (EAS)

AF:

0.00

AC:

AN:

28843

South Asian (SAS)

AF:

0.00

AC:

AN:

50387

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38824

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3821

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

746570

Other (OTH)

AF:

0.00

AC:

AN:

42124

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 2

Pathogenic:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CDKL5 disorder

Pathogenic:1

Jul 11, 2024

Centre for Population Genomics, CPG

Significance:Likely pathogenic

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 pathogenic. At least the following criteria are met: This variant is absent from gnomAD v4 (PM2_Supporting). Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). Occurs in the well-characterized ATP binding region of CDKL5 (PM1). Well-established in vitro or in vivo functional studies supportive of a damaging effect on the protein function (PS3). PMID: 29474534, PMID:20861382 , PMID:16935860 -

not provided

Pathogenic:1

Feb 15, 2011

RettBASE

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.19

T;T;.;T;.;.;.;.

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

1.0

.;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.91

D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.79

MutationAssessor

Pathogenic

3.5

M;.;.;M;.;.;.;M

PhyloP100

4.0

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-2.7

D;.;.;D;.;.;.;.

REVEL

Pathogenic

0.83

Sift

Uncertain

0.0010

D;.;.;D;.;.;.;.

Sift4G

Pathogenic

0.0

D;.;.;D;D;D;D;D

Polyphen

0.99

D;.;.;D;.;.;.;.

Vest4

0.77

MutPred

0.71

Loss of methylation at K42 (P = 8e-04);Loss of methylation at K42 (P = 8e-04);Loss of methylation at K42 (P = 8e-04);Loss of methylation at K42 (P = 8e-04);Loss of methylation at K42 (P = 8e-04);Loss of methylation at K42 (P = 8e-04);Loss of methylation at K42 (P = 8e-04);Loss of methylation at K42 (P = 8e-04);

MVP

0.97

MPC

2.3

ClinPred

0.99

GERP RS

4.8

Varity_R

0.94

gMVP

0.99

Mutation Taster

=11/89

disease causing (ClinVar)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over