chrX-18619898-C-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001323289.2(CDKL5):c.2308C>A(p.Gln770Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q770H) has been classified as Likely benign.

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

Uncertain significance criteria provided, single submitter U:1B:1

Conservation

PhyloP100: 4.42

Publications

0 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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.28485432).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CDKL5	NM_001323289.2 link	c.2308C>A	p.Gln770Lys	missense_variant	Exon 16 of 18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2 link	c.2308C>A	p.Gln770Lys	missense_variant	Exon 17 of 22		NP_001032420.1
CDKL5	NM_003159.3 link	c.2308C>A	p.Gln770Lys	missense_variant	Exon 16 of 21		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2 link	c.2308C>A	p.Gln770Lys	missense_variant	Exon 16 of 18	1	NM_001323289.2	ENSP00000485244.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1084280

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

351372

African (AFR)

AF:

0.00

AC:

AN:

26146

American (AMR)

AF:

0.00

AC:

AN:

35029

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19238

East Asian (EAS)

AF:

0.00

AC:

AN:

30070

South Asian (SAS)

AF:

0.00

AC:

AN:

53172

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40451

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4067

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

830472

Other (OTH)

AF:

0.00

AC:

AN:

45635

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

CDKL5 disorder

Uncertain:1

Jul 12, 2024

Centre for Population Genomics, CPG

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria. Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as a variant of uncertain significance. At least the following criteria are met: The variant is observed in at least 1 individual with no features of CDKL5 disorder (BS2_Supporting). PMID: 23064044 met Computational prediction analysis tools suggest no impact on gene product (REVEL score <= 0.15) (BP4). This variant is absent from gnomAD v4 (PM2_Supporting). -

not specified

Benign:1

May 09, 2014

RettBASE

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:curation

Inherited from unaffected mother, both proband and mother with random XCI; In silico prediction: SIFT = tolerated, MutationTaster = polymorphism, PolyPhen2 = benign, AlignGVGD = benign (C0) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.037

T;T;T;.;.

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.93

.;D;D;D;D

M_CAP

Pathogenic

0.69

MetaRNN

Benign

0.28

T;T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.7

L;.;L;.;L

PhyloP100

4.4

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-1.0

N;.;N;.;.

REVEL

Benign

0.092

Sift

Uncertain

0.022

D;.;D;.;.

Sift4G

Benign

0.081

T;.;T;T;T

Polyphen

0.43

B;.;B;.;.

Vest4

0.21

MutPred

0.11

Gain of ubiquitination at Q770 (P = 0.0117);Gain of ubiquitination at Q770 (P = 0.0117);Gain of ubiquitination at Q770 (P = 0.0117);Gain of ubiquitination at Q770 (P = 0.0117);Gain of ubiquitination at Q770 (P = 0.0117);

MVP

0.81

MPC

0.46

ClinPred

0.74

GERP RS

5.4

Varity_R

0.46

gMVP

0.23

Mutation Taster

=89/11

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over