chrX-18613242-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BS2_SupportingBA1

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Asn748Ser variant in CDKL5 is 0.03683% in African/African American 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.Asn748Ser variant is observed in at least 1 unaffected individual (PMID:29264392) (BS2_supporting). In summary, the p.Asn748Ser variant in CDKL5 is classified as Benign based on the ACMG/AMP criteria (BA1, BA2_supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA240506/MONDO:0100039/016

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., 3 hem., cov: 22)

Exomes 𝑓: 0.000048 ( 0 hom. 14 hem. )

Consequence

CDKL5
NM_001323289.2 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:2B:4

Conservation

PhyloP100: 2.91

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: Benign. The variant received -9 ACMG points.

BS2

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

BA1

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001323289.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CDKL5	NM_001323289.2	MANE Select	c.2243A>G	p.Asn748Ser	missense	Exon 15 of 18	NP_001310218.1
CDKL5	NM_001037343.2		c.2243A>G	p.Asn748Ser	missense	Exon 16 of 22	NP_001032420.1
CDKL5	NM_003159.3		c.2243A>G	p.Asn748Ser	missense	Exon 15 of 21	NP_003150.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CDKL5	ENST00000623535.2	TSL:1 MANE Select	c.2243A>G	p.Asn748Ser	missense	Exon 15 of 18	ENSP00000485244.1
CDKL5	ENST00000379989.6	TSL:1	c.2243A>G	p.Asn748Ser	missense	Exon 16 of 22	ENSP00000369325.3
CDKL5	ENST00000379996.7	TSL:1	c.2243A>G	p.Asn748Ser	missense	Exon 15 of 21	ENSP00000369332.3

Frequencies

GnomAD3 genomes

AF:

0.0000539

AC:

AN:

111318

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000163

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000280

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000491

AC:

AN:

183342

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.000380

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000722

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000366

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000476

AC:

AN:

1091612

Hom.:

Cov.:

AF XY:

0.0000391

AC XY:

AN XY:

357630

show subpopulations

African (AFR)

AF:

0.000190

AC:

AN:

26256

American (AMR)

AF:

0.00

AC:

AN:

35025

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19173

East Asian (EAS)

AF:

0.00

AC:

AN:

29807

South Asian (SAS)

AF:

0.00

AC:

AN:

53964

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39960

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4087

European-Non Finnish (NFE)

AF:

0.0000561

AC:

AN:

837614

Other (OTH)

AF:

0.00

AC:

AN:

45726

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

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:

0.0000539

AC:

AN:

111369

Hom.:

Cov.:

AF XY:

0.0000894

AC XY:

AN XY:

33545

show subpopulations

African (AFR)

AF:

0.000163

AC:

AN:

30656

American (AMR)

AF:

0.00

AC:

AN:

10475

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2634

East Asian (EAS)

AF:

0.000281

AC:

AN:

3557

South Asian (SAS)

AF:

0.00

AC:

AN:

2613

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5931

Middle Eastern (MID)

AF:

0.00

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53079

Other (OTH)

AF:

0.00

AC:

AN:

1518

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

Age Distribution

Genome 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

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000296

ClinVar

Significance: Benign

Submissions summary: Uncertain:2Benign:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Dec 09, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Missense variant in a gene in which most reported pathogenic variants are truncating/loss-of-function; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29264392)

May 26, 2014

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Developmental and epileptic encephalopathy, 2

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CDKL5 disorder

Benign:1

Feb 20, 2023

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The allele frequency of the p.Asn748Ser variant in CDKL5 is 0.03683% in African/African American 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.Asn748Ser variant is observed in at least 1 unaffected individual (PMID: 29264392) (BS2_supporting). In summary, the p.Asn748Ser variant in CDKL5 is classified as Benign based on the ACMG/AMP criteria (BA1, BA2_supporting).

Intellectual disability

Benign:1

Oct 24, 2019

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Benign:1

Dec 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.68

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.047

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.099

MetaRNN

Benign

0.062

MetaSVM

Benign

-0.76

MutationAssessor

Benign

1.2

PhyloP100

2.9

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.1

REVEL

Benign

0.20

Sift

Benign

0.068

Sift4G

Benign

0.14

Polyphen

0.43

Vest4

0.21

MutPred

0.068

Gain of phosphorylation at N748 (P = 0.0205)

MVP

0.85

MPC

0.43

ClinPred

0.061

GERP RS

5.0

Varity_R

0.24

gMVP

0.18

Mutation Taster

=83/17

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over