rs781427744

Positions:

chrX-18604488-T-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BS2BP5BS1

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Leu522Val variant in CDKL5 is 0.011% in European Non-Finnish sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). Additionally, the p.Leu522Val variant is observed in at least 2 unaffected individuals (internal database - GeneDx, internal database - Ambry Genetics) (BS2) and is found in a patient with an alternate molecular basis of disease (internal database - GeneDx) (BP5). In summary, the p.Leu522Val variant in CDKL5 is classified as Benign for CDKL5-associated disorder according to ACMG/AMP criteria (BS1, BS2, BP5). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10360394/MONDO:0100039/016

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.000025 ( 0 hom. 15 hem. )

Consequence

CDKL5
NM_001323289.2 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:4

Conservation

PhyloP100: 0.257

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 -9 ACMG points.

BP5

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

BS1

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

BS2

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CDKL5	NM_001323289.2 linkuse as main transcript	c.1564T>G	p.Leu522Val	missense_variant	12/18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2 linkuse as main transcript	c.1564T>G	p.Leu522Val	missense_variant	13/22		NP_001032420.1
CDKL5	NM_003159.3 linkuse as main transcript	c.1564T>G	p.Leu522Val	missense_variant	12/21		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2 linkuse as main transcript	c.1564T>G	p.Leu522Val	missense_variant	12/18	1	NM_001323289.2	ENSP00000485244	P1	O76039-2

Frequencies

GnomAD3 genomes

AF:

0.0000538

AC:

AN:

111544

Hom.:

Cov.:

AF XY:

0.0000593

AC XY:

AN XY:

33740

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:

0.000113

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000109

AC:

AN:

183420

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67866

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000244

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000246

AC:

AN:

1098189

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

363543

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000261

Gnomad4 OTH exome

AF:

0.0000868

GnomAD4 genome

AF:

0.0000538

AC:

AN:

111544

Hom.:

Cov.:

AF XY:

0.0000593

AC XY:

AN XY:

33740

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:

0.000113

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000174

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	CDKL5: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 2018	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 specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 19, 2016

- -

CDKL5 disorder

Benign:1

Benign, reviewed by expert panel

curation

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Feb 20, 2023

The allele frequency of the p.Leu522Val variant in CDKL5 is 0.011% in European Non-Finnish sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). Additionally, the p.Leu522Val variant is observed in at least 2 unaffected individuals (internal database - GeneDx, internal database - Ambry Genetics) (BS2) and is found in a patient with an alternate molecular basis of disease (internal database - GeneDx) (BP5). In summary, the p.Leu522Val variant in CDKL5 is classified as Benign for CDKL5-associated disorder according to ACMG/AMP criteria (BS1, BS2, BP5). -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 09, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.66

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.029

T;T;T;.;.

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.90

.;D;D;D;D

M_CAP

Benign

0.042

MetaRNN

Benign

0.072

T;T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.9

L;.;L;.;L

MutationTaster

Benign

0.95

N;N

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.26

N;.;N;.;.

REVEL

Benign

0.20

Sift

Benign

0.038

D;.;D;.;.

Sift4G

Benign

0.10

T;.;T;T;T

Polyphen

0.012

B;.;B;.;.

Vest4

0.15

MutPred

0.064

Gain of glycosylation at S519 (P = 0.0906);Gain of glycosylation at S519 (P = 0.0906);Gain of glycosylation at S519 (P = 0.0906);Gain of glycosylation at S519 (P = 0.0906);Gain of glycosylation at S519 (P = 0.0906);

MVP

0.60

MPC

0.58

ClinPred

0.051

GERP RS

0.51

Varity_R

0.079

gMVP

0.25

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