rs55803460

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS2

The NM_001323289.2(CDKL5):c.2200A>G(p.Thr734Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000625 in 1,200,245 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 28 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★).

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:4

Conservation

PhyloP100: 1.02

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1488162).

BP6

Variant X-18613199-A-G is Benign according to our data. Variant chrX-18613199-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 94108.Status of the report is reviewed_by_expert_panel, 3 stars.

BS2

High Hemizygotes in GnomAd at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CDKL5	NM_001323289.2 linkuse as main transcript	c.2200A>G	p.Thr734Ala	missense_variant	15/18	ENST00000623535.2
CDKL5	NM_001037343.2 linkuse as main transcript	c.2200A>G	p.Thr734Ala	missense_variant	16/22
CDKL5	NM_003159.3 linkuse as main transcript	c.2200A>G	p.Thr734Ala	missense_variant	15/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKL5	ENST00000623535.2 linkuse as main transcript	c.2200A>G	p.Thr734Ala	missense_variant	15/18	1	NM_001323289.2	P1	O76039-2

Frequencies

GnomAD3 genomes

AF:

0.0000990

AC:

AN:

111066

Hom.:

Cov.:

AF XY:

0.0000902

AC XY:

AN XY:

33252

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

GnomAD3 exomes

AF:

0.0000273

AC:

AN:

183371

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

67819

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 SAS exome

AF:

0.0000526

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000130

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000658

Gnomad4 OTH exome

AF:

0.0000438

GnomAD4 genome

AF:

0.0000990

AC:

AN:

111066

Hom.:

Cov.:

AF XY:

0.0000902

AC XY:

AN XY:

33252

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000208

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000174

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:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 08, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 11, 2020	This variant is associated with the following publications: (PMID: 23242510) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	CDKL5: BS2 -

Developmental and epileptic encephalopathy, 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

CDKL5 disorder

Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Sep 01, 2022

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;CN128785:Angelman syndrome-like

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Sep 19, 2023

- -

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

Dann

Benign

0.95

DEOGEN2

Benign

0.023

T;T;T;.;.

FATHMM_MKL

Uncertain

0.93

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

MutationTaster

Benign

1.0

N;N

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

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