rs55803460

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP5BS2BP4

This summary comes from the ClinGen Evidence Repository: 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). LINK:https://erepo.genome.network/evrepo/ui/classification/CA171623/MONDO:0100039/016

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:5

Conservation

PhyloP100: 1.02

Publications

9 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P
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

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

BP5

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

BS2

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	UniProt
CDKL5	NM_001323289.2	MANE Select	c.2200A>G	p.Thr734Ala	missense	Exon 15 of 18	NP_001310218.1	O76039-2
CDKL5	NM_001037343.2		c.2200A>G	p.Thr734Ala	missense	Exon 16 of 22	NP_001032420.1	O76039-1
CDKL5	NM_003159.3		c.2200A>G	p.Thr734Ala	missense	Exon 15 of 21	NP_003150.1	O76039-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDKL5	ENST00000623535.2	TSL:1 MANE Select	c.2200A>G	p.Thr734Ala	missense	Exon 15 of 18	ENSP00000485244.1	O76039-2
CDKL5	ENST00000379989.6	TSL:1	c.2200A>G	p.Thr734Ala	missense	Exon 16 of 22	ENSP00000369325.3	O76039-1
CDKL5	ENST00000379996.7	TSL:1	c.2200A>G	p.Thr734Ala	missense	Exon 15 of 21	ENSP00000369332.3	O76039-1

Frequencies

GnomAD3 genomes

AF:

0.0000990

AC:

AN:

111066

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.0000273

AC:

AN:

183371

AF XY:

0.0000442

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:

0.0000488

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

African (AFR)

AF:

0.00

AC:

AN:

26210

American (AMR)

AF:

0.00

AC:

AN:

35045

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19144

East Asian (EAS)

AF:

0.00

AC:

AN:

29825

South Asian (SAS)

AF:

0.000130

AC:

AN:

53911

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39965

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4098

European-Non Finnish (NFE)

AF:

0.0000658

AC:

AN:

835287

Other (OTH)

AF:

0.0000438

AC:

AN:

45694

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

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:

0.0000990

AC:

AN:

111066

Hom.:

Cov.:

AF XY:

0.0000902

AC XY:

AN XY:

33252

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30525

American (AMR)

AF:

0.00

AC:

AN:

10426

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2631

East Asian (EAS)

AF:

0.00

AC:

AN:

3565

South Asian (SAS)

AF:

0.00

AC:

AN:

2619

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5874

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.000208

AC:

AN:

53009

Other (OTH)

AF:

0.00

AC:

AN:

1493

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000108

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

ClinVar submissions as Germline

Significance:Likely benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

CDKL5 disorder (2)

Developmental and epileptic encephalopathy, 2 (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.59

CADD

Benign

9.2

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.023

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.68

M_CAP

Benign

0.032

MetaRNN

Benign

0.15

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.34

PhyloP100

1.0

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.23

REVEL

Benign

0.14

Sift

Uncertain

0.022

Sift4G

Benign

0.22

Polyphen

0.048

Vest4

0.042

MVP

0.66

MPC

0.34

ClinPred

0.036

GERP RS

0.24

Varity_R

0.055

gMVP

0.075

Mutation Taster

=98/2

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over