rs140332992

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP7BS2

This summary comes from the ClinGen Evidence Repository: The p.Arg31= variant in CDKL5 is present in 3 female and 2 male individuals in gnomAD (0.002%) (not sufficient to meet BS1 criteria). The p.Arg31= variant is observed in at least 2 unaffected individuals (internal database) (BS2). The silent p.Arg31= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). In summary, the p.Arg31= variant in CDKL5 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP7). LINK:https://erepo.genome.network/evrepo/ui/classification/CA171658/MONDO:0100039/016

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000024 ( 0 hom. 9 hem. )

Consequence

CDKL5
NM_001323289.2 synonymous

Scores

Clinical Significance

Likely benign reviewed by expert panel U:2B:5

Conservation

PhyloP100: 0.862

Publications

1 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 Gene-Disease associations (from GenCC):

CDKL5 disorder
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
developmental and epileptic encephalopathy, 2
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
atypical Rett syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
genetic developmental and epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
infantile spasms
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
precocious puberty
Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

CDKL5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP7

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 rank	MANE	Protein	UniProt
CDKL5	NM_001323289.2 link	c.93A>G	p.Arg31Arg	synonymous_variant	Exon 3 of 18	ENST00000623535.2	NP_001310218.1	O76039-2
CDKL5	NM_001037343.2 link	c.93A>G	p.Arg31Arg	synonymous_variant	Exon 4 of 22		NP_001032420.1	O76039-1
CDKL5	NM_003159.3 link	c.93A>G	p.Arg31Arg	synonymous_variant	Exon 3 of 21		NP_003150.1	O76039-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2 link	c.93A>G	p.Arg31Arg	synonymous_variant	Exon 3 of 18	1	NM_001323289.2	ENSP00000485244.1		O76039-2

Frequencies

GnomAD3 genomes

AF:

0.0000448

AC:

AN:

111724

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000975

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:

0.00424

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000219

AC:

AN:

182437

AF XY:

0.0000298

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000367

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000237

AC:

AN:

1057042

Hom.:

Cov.:

AF XY:

0.0000274

AC XY:

AN XY:

328494

show subpopulations

African (AFR)

AF:

0.000234

AC:

AN:

25668

American (AMR)

AF:

0.0000285

AC:

AN:

35142

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19097

East Asian (EAS)

AF:

0.00

AC:

AN:

29986

South Asian (SAS)

AF:

0.00

AC:

AN:

53145

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39971

Middle Eastern (MID)

AF:

0.000501

AC:

AN:

3996

European-Non Finnish (NFE)

AF:

0.0000199

AC:

AN:

805322

Other (OTH)

AF:

0.00

AC:

AN:

44715

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.0000447

AC:

AN:

111779

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33963

show subpopulations

African (AFR)

AF:

0.0000973

AC:

AN:

30836

American (AMR)

AF:

0.00

AC:

AN:

10473

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2649

East Asian (EAS)

AF:

0.00

AC:

AN:

3560

South Asian (SAS)

AF:

0.00

AC:

AN:

2666

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5979

Middle Eastern (MID)

AF:

0.00463

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53199

Other (OTH)

AF:

0.00

AC:

AN:

1517

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000453

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2Benign:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Mar 10, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CDKL5: BP4, BP7, BS2 -

Jun 19, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Aug 10, 2015

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CDKL5 disorder

Benign:1

Sep 01, 2022

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance:Likely benign

Review Status:reviewed by expert panel

Collection Method:curation

The p.Arg31= variant in CDKL5 is present in 3 female and 2 male individuals in gnomAD (0.002%) (not sufficient to meet BS1 criteria). The p.Arg31= variant is observed in at least 2 unaffected individuals (internal database) (BS2). The silent p.Arg31= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). In summary, the p.Arg31= variant in CDKL5 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP7). -

History of neurodevelopmental disorder

Benign:1

Jan 16, 2017

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico models in agreement (benign);Synonymous alterations with insufficient evidence to classify as benign -

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

Benign:1

Dec 22, 2024

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

BayesDel_noAF

Benign

-0.53

CADD

Benign

8.9

(source)

DANN

Benign

0.75

PhyloP100

0.86

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over