rs139155110

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The ENST00000379989.6(CDKL5):c.3084G>A(p.Thr1028=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00438 in 1,210,189 control chromosomes in the GnomAD database, including 20 homozygotes. There are 1,674 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. T1028T) has been classified as Uncertain significance.

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:12

Conservation

PhyloP100: -0.408

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant X-18653535-G-A is Benign according to our data. Variant chrX-18653535-G-A is described in ClinVar as [Benign]. Clinvar id is 94112.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chrX-18653535-G-A is described in Lovd as [Likely_benign]. Variant chrX-18653535-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.408 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0035 (394/112530) while in subpopulation NFE AF= 0.00433 (231/53308). AF 95% confidence interval is 0.00387. There are 2 homozygotes in gnomad4. There are 124 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
RS1	NM_000330.4 linkuse as main transcript	c.184+3118C>T		intron_variant		ENST00000379984.4
CDKL5	NM_001037343.2 linkuse as main transcript	c.3084G>A	p.Thr1028=	synonymous_variant	22/22
CDKL5	NM_003159.3 linkuse as main transcript	c.3084G>A	p.Thr1028=	synonymous_variant	21/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKL5	ENST00000379989.6 linkuse as main transcript	c.3084G>A	p.Thr1028=	synonymous_variant	22/22	1			O76039-1
CDKL5	ENST00000379996.7 linkuse as main transcript	c.3084G>A	p.Thr1028=	synonymous_variant	21/21	1			O76039-1
RS1	ENST00000379984.4 linkuse as main transcript	c.184+3118C>T		intron_variant		1	NM_000330.4	P1
CDKL5	ENST00000673617.1 linkuse as main transcript	n.356G>A		non_coding_transcript_exon_variant	3/3

Frequencies

GnomAD3 genomes

AF:

0.00352

AC:

396

AN:

112477

Hom.:

Cov.:

AF XY:

0.00361

AC XY:

125

AN XY:

34629

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

GnomAD3 exomes

AF:

0.00415

AC:

754

AN:

181578

Hom.:

AF XY:

0.00397

AC XY:

263

AN XY:

66190

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 SAS exome

AF:

0.00111

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

Gnomad4 AFR exome

AF:

0.000985

Gnomad4 AMR exome

AF:

0.00207

Gnomad4 ASJ exome

AF:

0.0268

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.00128

Gnomad4 FIN exome

AF:

0.00382

Gnomad4 NFE exome

AF:

0.00450

Gnomad4 OTH exome

AF:

0.00521

GnomAD4 genome

AF:

0.00350

AC:

394

AN:

112530

Hom.:

Cov.:

AF XY:

0.00357

AC XY:

124

AN XY:

34692

show subpopulations

Gnomad4 AFR

AF:

0.000774

Gnomad4 AMR

AF:

0.00113

Gnomad4 ASJ

AF:

0.0294

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00290

Gnomad4 FIN

AF:

0.00438

Gnomad4 NFE

AF:

0.00433

Gnomad4 OTH

AF:

0.00522

Alfa

AF:

0.00629

Hom.:

Bravo

AF:

0.00330

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:12

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	curation	RettBASE	May 15, 2014	Silent mutation, often found in cis with c.145+17A>G and c.3003G>A (p.H1001H) -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 11, 2012	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 15, 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. -

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Developmental and epileptic encephalopathy, 2

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

- -

CDKL5 disorder

Benign:1

Benign, reviewed by expert panel

curation

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Aug 25, 2022

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). -

CDKL5-related condition

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 03, 2019

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). -

History of neurodevelopmental disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 27, 2016

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. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

Cadd

Benign

0.16

Dann

Benign

0.56

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