rs398123694

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_003159.3(CDKL5):c.2653G>A(p.Gly885Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000578 in 1,210,322 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G885G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.0000055 ( 0 hom. 1 hem. )

Consequence

CDKL5
NM_003159.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 2.74

Publications

5 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 -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2190513).

BS2

High AC in GnomAdExome4 at 6 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003159.3. 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.2653G>A	p.Gly885Arg	missense	Exon 18 of 18	NP_001310218.1
CDKL5	NM_001037343.2		c.2653G>A	p.Gly885Arg	missense	Exon 19 of 22	NP_001032420.1
CDKL5	NM_003159.3		c.2653G>A	p.Gly885Arg	missense	Exon 18 of 21	NP_003150.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CDKL5	ENST00000623535.2	TSL:1 MANE Select	c.2653G>A	p.Gly885Arg	missense	Exon 18 of 18	ENSP00000485244.1
CDKL5	ENST00000379989.6	TSL:1	c.2653G>A	p.Gly885Arg	missense	Exon 19 of 22	ENSP00000369325.3
CDKL5	ENST00000379996.7	TSL:1	c.2653G>A	p.Gly885Arg	missense	Exon 18 of 21	ENSP00000369332.3

Frequencies

GnomAD3 genomes

AF:

0.00000892

AC:

AN:

112080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000324

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000546

AC:

AN:

183311

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000546

AC:

AN:

1098242

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363596

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26403

American (AMR)

AF:

0.00

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19386

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.0000369

AC:

AN:

54148

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40530

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.00000475

AC:

AN:

842129

Other (OTH)

AF:

0.00

AC:

AN:

46096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.00000892

AC:

AN:

112080

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34250

show subpopulations

African (AFR)

AF:

0.0000324

AC:

AN:

30901

American (AMR)

AF:

0.00

AC:

AN:

10603

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2650

East Asian (EAS)

AF:

0.00

AC:

AN:

3554

South Asian (SAS)

AF:

0.00

AC:

AN:

2700

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6079

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53178

Other (OTH)

AF:

0.00

AC:

AN:

1498

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Developmental and epileptic encephalopathy, 2 (1)

Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like (1)

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.049

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.81

M_CAP

Pathogenic

0.37

MetaRNN

Benign

0.22

MetaSVM

Benign

-0.67

MutationAssessor

Benign

1.6

PhyloP100

2.7

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.93

REVEL

Benign

0.18

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.025

Polyphen

0.99

Vest4

0.24

MutPred

0.17

Gain of solvent accessibility (P = 0.0097)

MVP

0.71

MPC

0.44

ClinPred

0.58

GERP RS

3.9

Varity_R

0.43

gMVP

0.40

Mutation Taster

=85/15

polymorphism

(source)

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

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over