rs35693326

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000379989.6(CDKL5):c.2995G>A(p.Val999Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00565 in 1,209,251 control chromosomes in the GnomAD database, including 257 homozygotes. There are 1,817 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V999V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.029 ( 140 hom., 800 hem., cov: 23)

Exomes 𝑓: 0.0033 ( 117 hom. 1017 hem. )

Consequence

CDKL5
ENST00000379989.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: -0.515

Publications

13 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002029866).

BP6

Variant X-18653446-G-A is Benign according to our data. Variant chrX-18653446-G-A is described in ClinVar as Benign. ClinVar VariationId is 94110.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0971 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
RS1	NM_000330.4 link	c.184+3207C>T		intron_variant	Intron 3 of 5	ENST00000379984.4	NP_000321.1
CDKL5	NM_001037343.2 link	c.2995G>A	p.Val999Met	missense_variant	Exon 22 of 22		NP_001032420.1
CDKL5	NM_003159.3 link	c.2995G>A	p.Val999Met	missense_variant	Exon 21 of 21		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CDKL5	ENST00000379989.6 link	c.2995G>A	p.Val999Met	missense_variant	Exon 22 of 22	1		ENSP00000369325.3
CDKL5	ENST00000379996.7 link	c.2995G>A	p.Val999Met	missense_variant	Exon 21 of 21	1		ENSP00000369332.3
RS1	ENST00000379984.4 link	c.184+3207C>T		intron_variant	Intron 3 of 5	1	NM_000330.4	ENSP00000369320.3
CDKL5	ENST00000673617.1 link	n.267G>A		non_coding_transcript_exon_variant	Exon 3 of 3

Frequencies

GnomAD3 genomes

AF:

0.0287

AC:

3203

AN:

111478

Hom.:

140

Cov.:

show subpopulations

Gnomad AFR

AF:

0.100

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00888

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00111

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00422

Gnomad NFE

AF:

0.000320

Gnomad OTH

AF:

0.0214

GnomAD2 exomes

AF:

0.00851

AC:

1548

AN:

181957

AF XY:

0.00583

show subpopulations

Gnomad AFR exome

AF:

0.104

Gnomad AMR exome

AF:

0.00494

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000407

Gnomad OTH exome

AF:

0.00244

GnomAD4 exome

AF:

0.00330

AC:

3622

AN:

1097724

Hom.:

117

Cov.:

AF XY:

0.00280

AC XY:

1017

AN XY:

363130

show subpopulations

African (AFR)

AF:

0.108

AC:

2842

AN:

26390

American (AMR)

AF:

0.00552

AC:

194

AN:

35174

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19380

East Asian (EAS)

AF:

0.00

AC:

AN:

30193

South Asian (SAS)

AF:

0.000629

AC:

AN:

54077

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40425

Middle Eastern (MID)

AF:

0.00642

AC:

AN:

4051

European-Non Finnish (NFE)

AF:

0.000227

AC:

191

AN:

841972

Other (OTH)

AF:

0.00727

AC:

335

AN:

46062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

169

337

506

674

843

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

176

264

352

440

<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:

0.0288

AC:

3207

AN:

111527

Hom.:

140

Cov.:

AF XY:

0.0237

AC XY:

800

AN XY:

33733

show subpopulations

African (AFR)

AF:

0.100

AC:

3061

AN:

30594

American (AMR)

AF:

0.00886

AC:

AN:

10491

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2651

East Asian (EAS)

AF:

0.00

AC:

AN:

3517

South Asian (SAS)

AF:

0.00112

AC:

AN:

2685

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6022

Middle Eastern (MID)

AF:

0.00463

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.000320

AC:

AN:

53155

Other (OTH)

AF:

0.0212

AC:

AN:

1511

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

106

212

319

425

531

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.0102

Hom.:

407

Bravo

AF:

0.0332

ESP6500AA

AF:

0.106

AC:

408

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.00973

AC:

1181

EpiCase

AF:

0.000491

EpiControl

AF:

0.000715

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:9

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 05, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 09, 2014

RettBASE

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:curation

Found in unaffected mother with apparent balanced X-chromosome inactivation; in exon 20, affecting only the transcript lowly expressed; In silico prediction: SIFT = tolerated, MutationTaster = polymorphism, PolyPhen2 = benign, AlignGVGD = benign (C0) -

Feb 13, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 05, 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. -

not provided

Benign:2

Jan 11, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

CDKL5 disorder

Benign:1

Sep 20, 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 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). -

West syndrome

Benign:1

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

History of neurodevelopmental disorder

Benign:1

Sep 13, 2019

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance -

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

Benign:1

Feb 03, 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

0.21

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.74

CADD

Benign

8.9

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.032

T;T

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.49

.;T

MetaRNN

Benign

0.0020

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;N

PhyloP100

-0.52

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.22

N;N

REVEL

Benign

0.034

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.28

B;B

Vest4

0.093

MVP

0.28

MPC

0.78

ClinPred

0.037

GERP RS

-0.0082

Varity_R

0.085

gMVP

0.035

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

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over