rs587783162

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS2

The ENST00000379989.6(CDKL5):c.3008T>C(p.Met1003Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,209,625 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000082 ( 0 hom. 3 hem. )

Consequence

CDKL5
ENST00000379989.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: -0.375

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 links:

RS1 (HGNC:10457): (retinoschisin 1) This gene encodes an extracellular protein that plays a crucial role in the cellular organization of the retina. The encoded protein is assembled and secreted from photoreceptors and bipolar cells as a homo-oligomeric protein complex. Mutations in this gene are responsible for X-linked retinoschisis, a common, early-onset macular degeneration in males that results in a splitting of the inner layers of the retina and severe loss in vision. [provided by RefSeq, Oct 2008]

RS1 Gene-Disease associations (from GenCC):

retinoschisis
Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
X-linked retinoschisis
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, ClinGen

RS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10630739).

BP6

Variant X-18653459-T-C is Benign according to our data. Variant chrX-18653459-T-C is described in ClinVar as Benign. ClinVar VariationId is 156695.Status of the report is reviewed_by_expert_panel, 3 stars.

BS2

High AC in GnomAdExome4 at 9 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RS1	NM_000330.4 link	c.184+3194A>G		intron_variant	Intron 3 of 5	ENST00000379984.4	NP_000321.1	O15537
CDKL5	NM_001037343.2 link	c.3008T>C	p.Met1003Thr	missense_variant	Exon 22 of 22		NP_001032420.1	O76039-1
CDKL5	NM_003159.3 link	c.3008T>C	p.Met1003Thr	missense_variant	Exon 21 of 21		NP_003150.1	O76039-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CDKL5	ENST00000379989.6 link	c.3008T>C	p.Met1003Thr	missense_variant	Exon 22 of 22	1		ENSP00000369325.3	O76039-1
CDKL5	ENST00000379996.7 link	c.3008T>C	p.Met1003Thr	missense_variant	Exon 21 of 21	1		ENSP00000369332.3	O76039-1
RS1	ENST00000379984.4 link	c.184+3194A>G		intron_variant	Intron 3 of 5	1	NM_000330.4	ENSP00000369320.3	O15537
CDKL5	ENST00000673617.1 link	n.280T>C		non_coding_transcript_exon_variant	Exon 3 of 3

Frequencies

GnomAD3 genomes

AF:

0.0000269

AC:

AN:

111650

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:

0.0000564

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000820

AC:

AN:

1097975

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

363351

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26392

American (AMR)

AF:

0.00

AC:

AN:

35199

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19384

East Asian (EAS)

AF:

0.00

AC:

AN:

30196

South Asian (SAS)

AF:

0.00

AC:

AN:

54119

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40478

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4079

European-Non Finnish (NFE)

AF:

0.0000107

AC:

AN:

842047

Other (OTH)

AF:

0.00

AC:

AN:

46081

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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:

0.0000269

AC:

AN:

111650

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33814

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30677

American (AMR)

AF:

0.00

AC:

AN:

10500

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2647

East Asian (EAS)

AF:

0.00

AC:

AN:

3539

South Asian (SAS)

AF:

0.00

AC:

AN:

2683

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6034

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.0000564

AC:

AN:

53162

Other (OTH)

AF:

0.00

AC:

AN:

1486

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:2

Feb 19, 2014

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 21, 2016

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

CDKL5-related disorder

Uncertain:1

Aug 25, 2022

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CDKL5 c.3008T>C variant is predicted to result in the amino acid substitution p.Met1003Thr. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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

Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.67

CADD

Benign

1.1

(source)

DANN

Benign

0.56

DEOGEN2

Benign

0.031

T;T

FATHMM_MKL

Benign

0.030

LIST_S2

Benign

0.34

.;T

M_CAP

Pathogenic

0.39

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.0

N;N

PhyloP100

-0.38

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.30

N;N

REVEL

Benign

0.12

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.0010

B;B

Vest4

0.18

MutPred

0.37

Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);

MVP

0.18

MPC

0.42

ClinPred

0.090

GERP RS

0.45

Varity_R

0.45

gMVP

0.13

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over