rs35693326

Positions:

Variant summary

Our verdict is Benign. Variant got -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. 12/18 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 94110.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18653446-G-A is described in Lovd as [Benign].

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/exons	MANE	Protein
RS1	NM_000330.4 linkuse as main transcript	c.184+3207C>T		intron_variant		ENST00000379984.4	NP_000321.1
CDKL5	NM_001037343.2 linkuse as main transcript	c.2995G>A	p.Val999Met	missense_variant	22/22		NP_001032420.1
CDKL5	NM_003159.3 linkuse as main transcript	c.2995G>A	p.Val999Met	missense_variant	21/21		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000379989.6 linkuse as main transcript	c.2995G>A	p.Val999Met	missense_variant	22/22	1		ENSP00000369325		O76039-1
CDKL5	ENST00000379996.7 linkuse as main transcript	c.2995G>A	p.Val999Met	missense_variant	21/21	1		ENSP00000369332		O76039-1
RS1	ENST00000379984.4 linkuse as main transcript	c.184+3207C>T		intron_variant		1	NM_000330.4	ENSP00000369320	P1
CDKL5	ENST00000673617.1 linkuse as main transcript	n.267G>A		non_coding_transcript_exon_variant	3/3

Frequencies

GnomAD3 genomes

AF:

0.0287

AC:

3203

AN:

111478

Hom.:

140

Cov.:

AF XY:

0.0237

AC XY:

799

AN XY:

33674

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

GnomAD3 exomes

AF:

0.00851

AC:

1548

AN:

181957

Hom.:

AF XY:

0.00583

AC XY:

388

AN XY:

66519

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 SAS exome

AF:

0.000688

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

Gnomad4 AFR exome

AF:

0.108

Gnomad4 AMR exome

AF:

0.00552

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000629

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000227

Gnomad4 OTH exome

AF:

0.00727

GnomAD4 genome

AF:

0.0288

AC:

3207

AN:

111527

Hom.:

140

Cov.:

AF XY:

0.0237

AC XY:

800

AN XY:

33733

show subpopulations

Gnomad4 AFR

AF:

0.100

Gnomad4 AMR

AF:

0.00886

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00112

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000320

Gnomad4 OTH

AF:

0.0212

Alfa

AF:

0.00407

Hom.:

105

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

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 05, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 05, 2012	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	curation	RettBASE	May 09, 2014	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) -
Benign, no assertion criteria provided	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Feb 13, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 11, 2016	- -

CDKL5 disorder

Benign:1

Benign, criteria provided, single submitter

curation

Centre for Population Genomics, CPG

Sep 20, 2024

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

Benign, criteria provided, single submitter

clinical testing

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

Nov 01, 2016

- -

History of neurodevelopmental disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 13, 2019

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.74

CADD

Benign

8.9

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

MutationTaster

Benign

1.0

P;P;P

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over