X-18653535-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BS2BA1

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Thr1028= variant in CDKL5 is 2.6% in Ashkenazi Jewish sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Thr1028= variant is observed in at least 2 unaffected individuals (internal database, BS2). In summary, the p.Thr1028= variant in CDKL5 is classified as benign based on the ACMG/AMP criteria (BA1, BS2). LINK:https://erepo.genome.network/evrepo/ui/classification/CA147633/MONDO:0100039/016

Frequency

Genomes: 𝑓 0.0035 ( 2 hom., 124 hem., cov: 23)

Exomes 𝑓: 0.0045 ( 18 hom. 1550 hem. )

Consequence

CDKL5
ENST00000379989.6 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:14

Conservation

PhyloP100: -0.408

Publications

2 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 links:

RS1 (HGNC:10457): (retinoschisin 1) This gene encodes an extracellular protein that plays a crucial role in the cellular organization of the retina. The encoded protein is assembled and secreted from photoreceptors and bipolar cells as a homo-oligomeric protein complex. Mutations in this gene are responsible for X-linked retinoschisis, a common, early-onset macular degeneration in males that results in a splitting of the inner layers of the retina and severe loss in vision. [provided by RefSeq, Oct 2008]

RS1 Gene-Disease associations (from GenCC):

retinoschisis
Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
X-linked retinoschisis
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, ClinGen

RS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BS2

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

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RS1	NM_000330.4 link	c.184+3118C>T		intron_variant	Intron 3 of 5	ENST00000379984.4	NP_000321.1	O15537
CDKL5	NM_001037343.2 link	c.3084G>A	p.Thr1028Thr	synonymous_variant	Exon 22 of 22		NP_001032420.1	O76039-1
CDKL5	NM_003159.3 link	c.3084G>A	p.Thr1028Thr	synonymous_variant	Exon 21 of 21		NP_003150.1	O76039-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CDKL5	ENST00000379989.6 link	c.3084G>A	p.Thr1028Thr	synonymous_variant	Exon 22 of 22	1		ENSP00000369325.3	O76039-1
CDKL5	ENST00000379996.7 link	c.3084G>A	p.Thr1028Thr	synonymous_variant	Exon 21 of 21	1		ENSP00000369332.3	O76039-1
RS1	ENST00000379984.4 link	c.184+3118C>T		intron_variant	Intron 3 of 5	1	NM_000330.4	ENSP00000369320.3	O15537
CDKL5	ENST00000673617.1 link	n.356G>A		non_coding_transcript_exon_variant	Exon 3 of 3

Frequencies

GnomAD3 genomes

AF:

0.00352

AC:

396

AN:

112477

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000776

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00113

Gnomad ASJ

AF:

0.0294

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00289

Gnomad FIN

AF:

0.00438

Gnomad MID

AF:

0.0252

Gnomad NFE

AF:

0.00437

Gnomad OTH

AF:

0.00528

GnomAD2 exomes

AF:

0.00415

AC:

754

AN:

181578

AF XY:

0.00397

show subpopulations

Gnomad AFR exome

AF:

0.000846

Gnomad AMR exome

AF:

0.00201

Gnomad ASJ exome

AF:

0.0257

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00301

Gnomad NFE exome

AF:

0.00495

Gnomad OTH exome

AF:

0.00622

GnomAD4 exome

AF:

0.00447

AC:

4906

AN:

1097659

Hom.:

Cov.:

AF XY:

0.00427

AC XY:

1550

AN XY:

363033

show subpopulations

African (AFR)

AF:

0.000985

AC:

AN:

26390

American (AMR)

AF:

0.00207

AC:

AN:

35182

Ashkenazi Jewish (ASJ)

AF:

0.0268

AC:

519

AN:

19375

East Asian (EAS)

AF:

0.0000331

AC:

AN:

30190

South Asian (SAS)

AF:

0.00128

AC:

AN:

54053

European-Finnish (FIN)

AF:

0.00382

AC:

154

AN:

40351

Middle Eastern (MID)

AF:

0.00799

AC:

AN:

4128

European-Non Finnish (NFE)

AF:

0.00450

AC:

3791

AN:

841915

Other (OTH)

AF:

0.00521

AC:

240

AN:

46075

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

215

430

645

860

1075

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

146

292

438

584

730

<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:

0.00350

AC:

394

AN:

112530

Hom.:

Cov.:

AF XY:

0.00357

AC XY:

124

AN XY:

34692

show subpopulations

African (AFR)

AF:

0.000774

AC:

AN:

31003

American (AMR)

AF:

0.00113

AC:

AN:

10638

Ashkenazi Jewish (ASJ)

AF:

0.0294

AC:

AN:

2652

East Asian (EAS)

AF:

0.00

AC:

AN:

3566

South Asian (SAS)

AF:

0.00290

AC:

AN:

2761

European-Finnish (FIN)

AF:

0.00438

AC:

AN:

6162

Middle Eastern (MID)

AF:

0.0275

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00433

AC:

231

AN:

53308

Other (OTH)

AF:

0.00522

AC:

AN:

1534

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

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:

0.00629

Hom.:

Bravo

AF:

0.00330

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:14

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:6

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 15, 2012

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 11, 2012

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 15, 2014

RettBASE

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:curation

Silent mutation, often found in cis with c.145+17A>G and c.3003G>A (p.H1001H) -

not provided

Uncertain:1Benign:1

Jun 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Developmental and epileptic encephalopathy, 2

Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 16, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CDKL5 disorder

Benign:2

Jul 02, 2024

Centre for Population Genomics, CPG

Significance: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 benign. At least the following criteria are met: The allele frequency of this variant in at least one population in gnomAD v3 is higher than the 0.03% threshold defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders VCEP 3.0 (BA1). -

Aug 25, 2022

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The allele frequency of the p.Thr1028= variant in CDKL5 is 2.6% in Ashkenazi Jewish sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Thr1028= variant is observed in at least 2 unaffected individuals (internal database, BS2). In summary, the p.Thr1028= variant in CDKL5 is classified as benign based on the ACMG/AMP criteria (BA1, BS2). -

History of neurodevelopmental disorder

Benign:1

Jul 27, 2016

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

CDKL5-related disorder

Benign:1

Apr 03, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Benign:1

Jan 30, 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

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.16

(source)

DANN

Benign

0.56

PhyloP100

-0.41

Mutation Taster

=100/0

polymorphism (auto)

(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