rs55803460

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP5BS2BP4

This summary comes from the ClinGen Evidence Repository: The p.Thr734Ala variant in CDKL5 is present in 7 female and male individuals in gnomAD (0.003%) (not sufficient to meet BS1 criteria). The p.Thr734Ala variant is observed in at least 2 unaffected individuals (internal database) (BS2). Computational analysis prediction tools suggest that the p.Thr734Ala variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). The p.Thr734Ala variant is found in a patient with an alternate molecular basis of disease (internal database) (BP5). In summary, the p.Thr734Ala variant in CDKL5 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP4, BP5). LINK:https://erepo.genome.network/evrepo/ui/classification/CA171623/MONDO:0100039/016

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., 3 hem., cov: 22)

Exomes 𝑓: 0.000059 ( 0 hom. 25 hem. )

Consequence

CDKL5
NM_001323289.2 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:2B:5

Conservation

PhyloP100: 1.02

Publications

9 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 -6 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BP5

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.2200A>G	p.Thr734Ala	missense_variant	Exon 15 of 18	ENST00000623535.2	NP_001310218.1	O76039-2
CDKL5	NM_001037343.2 link	c.2200A>G	p.Thr734Ala	missense_variant	Exon 16 of 22		NP_001032420.1	O76039-1
CDKL5	NM_003159.3 link	c.2200A>G	p.Thr734Ala	missense_variant	Exon 15 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.2200A>G	p.Thr734Ala	missense_variant	Exon 15 of 18	1	NM_001323289.2	ENSP00000485244.1		O76039-2

Frequencies

GnomAD3 genomes

AF:

0.0000990

AC:

AN:

111066

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:

0.000208

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000273

AC:

AN:

183371

AF XY:

0.0000442

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:

0.0000488

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000588

AC:

AN:

1089179

Hom.:

Cov.:

AF XY:

0.0000704

AC XY:

AN XY:

355291

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26210

American (AMR)

AF:

0.00

AC:

AN:

35045

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19144

East Asian (EAS)

AF:

0.00

AC:

AN:

29825

South Asian (SAS)

AF:

0.000130

AC:

AN:

53911

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39965

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4098

European-Non Finnish (NFE)

AF:

0.0000658

AC:

AN:

835287

Other (OTH)

AF:

0.0000438

AC:

AN:

45694

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

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:

0.0000990

AC:

AN:

111066

Hom.:

Cov.:

AF XY:

0.0000902

AC XY:

AN XY:

33252

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30525

American (AMR)

AF:

0.00

AC:

AN:

10426

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2631

East Asian (EAS)

AF:

0.00

AC:

AN:

3565

South Asian (SAS)

AF:

0.00

AC:

AN:

2619

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5874

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.000208

AC:

AN:

53009

Other (OTH)

AF:

0.00

AC:

AN:

1493

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.000108

Hom.:

Bravo

AF:

0.0000907

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2Benign:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Apr 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CDKL5: BS2 -

Jul 08, 2014

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 11, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 23242510) -

CDKL5 disorder

Benign:2

Sep 16, 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 allele frequency of this variant in at least one population in gnomAD is between 0.008% and 0.03% (BS1). Computational prediction analysis tools suggest no impact on gene product (REVEL score <= 0.15) (BP4). -

Sep 01, 2022

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance:Likely benign

Review Status:reviewed by expert panel

Collection Method:curation

The p.Thr734Ala variant in CDKL5 is present in 7 female and male individuals in gnomAD (0.003%) (not sufficient to meet BS1 criteria). The p.Thr734Ala variant is observed in at least 2 unaffected individuals (internal database) (BS2). Computational analysis prediction tools suggest that the p.Thr734Ala variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). The p.Thr734Ala variant is found in a patient with an alternate molecular basis of disease (internal database) (BP5). In summary, the p.Thr734Ala variant in CDKL5 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP4, BP5). -

Developmental and epileptic encephalopathy, 2

Uncertain:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like

Benign:1

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.59

CADD

Benign

9.2

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.023

T;T;T;.;.

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.68

.;T;T;T;T

M_CAP

Benign

0.032

MetaRNN

Benign

0.15

T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.34

N;.;N;.;N

PhyloP100

1.0

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.23

N;.;N;.;.

REVEL

Benign

0.14

Sift

Uncertain

0.022

D;.;D;.;.

Sift4G

Benign

0.22

T;.;T;T;T

Polyphen

0.048

B;.;B;.;.

Vest4

0.042

MVP

0.66

MPC

0.34

ClinPred

0.036

GERP RS

0.24

Varity_R

0.055

gMVP

0.075

Mutation Taster

=98/2

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over