rs267608418

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate

The NM_001323289.2(CDKL5):c.58G>A(p.Gly20Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G20V) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

CDKL5
NM_001323289.2 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 8.37

Publications

4 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: Pathogenic. The variant received 12 ACMG points.

PM1

In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001323289.2

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-18507155-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 918032.Status of the report is reviewed_by_expert_panel, 3 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.986

PP5

Variant X-18507154-G-A is Pathogenic according to our data. Variant chrX-18507154-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 844687.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKL5	NM_001323289.2 link	c.58G>A	p.Gly20Ser	missense_variant	Exon 2 of 18	ENST00000623535.2	NP_001310218.1	O76039-2
CDKL5	NM_001037343.2 link	c.58G>A	p.Gly20Ser	missense_variant	Exon 3 of 22		NP_001032420.1	O76039-1
CDKL5	NM_003159.3 link	c.58G>A	p.Gly20Ser	missense_variant	Exon 2 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.58G>A	p.Gly20Ser	missense_variant	Exon 2 of 18	1	NM_001323289.2	ENSP00000485244.1		O76039-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1075371

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

342317

African (AFR)

AF:

0.00

AC:

AN:

25973

American (AMR)

AF:

0.00

AC:

AN:

35171

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19228

East Asian (EAS)

AF:

0.00

AC:

AN:

30098

South Asian (SAS)

AF:

0.00

AC:

AN:

53595

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40514

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4050

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

821370

Other (OTH)

AF:

0.00

AC:

AN:

45372

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Pathogenic:1

Jan 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has not been reported in the literature in individuals affected with CDKL5-related conditions. ClinVar contains an entry for this variant (Variation ID: 844687). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CDKL5 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Gly20 amino acid residue in CDKL5. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20397747, 23064044, 29420175). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 20 of the CDKL5 protein (p.Gly20Ser). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

T;T;.;T;.;.;.;.

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

.;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.90

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.65

MutationAssessor

Uncertain

2.8

M;.;.;M;.;.;.;M

PhyloP100

8.4

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-4.7

D;.;.;D;.;.;.;.

REVEL

Pathogenic

0.87

Sift

Uncertain

0.0040

D;.;.;D;.;.;.;.

Sift4G

Uncertain

0.027

D;.;.;D;D;D;D;D

Polyphen

1.0

D;.;.;D;.;.;.;.

Vest4

0.87

MutPred

0.93

Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);

MVP

0.99

MPC

2.6

ClinPred

1.0

GERP RS

4.7

Varity_R

0.95

gMVP

0.91

Mutation Taster

=7/93

disease causing

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over