chrX-18587977-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM6_StrongPM2_SupportingPP3PP4PP1

This summary comes from the ClinGen Evidence Repository: The p.Asp193Gly variant in CDKL5 has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in affected individuals (PMID 23583054) (PM6_Strong). The p.Asp193Gly variant in CDKL5 is absent from gnomAD (PM2_Supporting). The variant has been reported to segregate in two informative meioses (PMID:23583054) (PP1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Asp193Gly variant in CDKL5 has been reported in an individual with a clinical phenotype suggestive of a CDKL5-associated disorder (PP4). In summary, the p.Asp193Gly variant in CDKL5 is classified as likely pathogenic for CDKL5-associated disorder based on the ACMG/AMP criteria (PM6_strong, PM2_supporting, PP1, PP3, PP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA171648/MONDO:0100039/016

Frequency

Genomes: not found (cov: 23)
Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )

Consequence

CDKL5
ENST00000623535.2 missense

Scores

12
3
2

Clinical Significance

Likely pathogenic reviewed by expert panel P:5

Conservation

PhyloP100: 8.95
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2
For more information check the summary or visit ClinGen Evidence Repository.
PM6
For more information check the summary or visit ClinGen Evidence Repository.
PP1
For more information check the summary or visit ClinGen Evidence Repository.
PP3
For more information check the summary or visit ClinGen Evidence Repository.
PP4
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CDKL5NM_001323289.2 linkuse as main transcriptc.578A>G p.Asp193Gly missense_variant 9/18 ENST00000623535.2 NP_001310218.1
CDKL5NM_001037343.2 linkuse as main transcriptc.578A>G p.Asp193Gly missense_variant 10/22 NP_001032420.1
CDKL5NM_003159.3 linkuse as main transcriptc.578A>G p.Asp193Gly missense_variant 9/21 NP_003150.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CDKL5ENST00000623535.2 linkuse as main transcriptc.578A>G p.Asp193Gly missense_variant 9/181 NM_001323289.2 ENSP00000485244 P1O76039-2

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
AF:
9.11e-7
AC:
1
AN:
1097378
Hom.:
0
Cov.:
29
AF XY:
0.00000276
AC XY:
1
AN XY:
362786
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000119
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
23

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:5
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 2 Pathogenic:2
Pathogenic, no assertion criteria providedcurationRettBASEMar 13, 2014Mutation also found in affected half-siblings, likely maternal germline mosaicism; mutation not seen in asymptomatic mother; highly conserved amino acid, in catalytic domain; In silico prediction: SIFT = deleterious, MutationTaster = disease-causing, PolyPhen2 = probably damaging, AlignGVGD = pathogenic (C65) -
Pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoFeb 08, 2013- -
CDKL5 disorder Pathogenic:2
Likely pathogenic, criteria provided, single submittercurationCentre for Population Genomics, CPGJul 11, 2024This 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 likely pathogenic. At least the following criteria are met: Another missense variant in the same codon has been classified as pathogenic (PM5) Variation ID: 1432338, PMID: 29655203 PMID: 27781031 Co-segregation with disease in multiple affected family members in at least 2 informative meiosis (PP1). 23583054 Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). At least one individual with this variant has been reported with a clinical phenotype consistent with CDKL5- related condition (PP4). PMID 23583054 This variant is absent from gnomAD v2/v3 (PM2_Supporting). Has been observed in at least 2 individuals with phenotypes consistent with CDKL5 disorder (PS4_Supporting). -
Likely pathogenic, reviewed by expert panelcurationClinGen Rett and Angelman-like Disorders Variant Curation Expert PanelMar 26, 2021The p.Asp193Gly variant in CDKL5 has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in affected individuals (PMID 23583054) (PM6_Strong). The p.Asp193Gly variant in CDKL5 is absent from gnomAD (PM2_Supporting). The variant has been reported to segregate in two informative meioses (PMID: 23583054) (PP1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Asp193Gly variant in CDKL5 has been reported in an individual with a clinical phenotype suggestive of a CDKL5-associated disorder (PP4). In summary, the p.Asp193Gly variant in CDKL5 is classified as likely pathogenic for CDKL5-associated disorder based on the ACMG/AMP criteria (PM6_strong, PM2_supporting, PP1, PP3, PP4). -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJul 01, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.53
D
BayesDel_noAF
Pathogenic
0.53
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Benign
0.35
T;T;.;T;.;.
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
.;D;D;D;D;D
M_CAP
Pathogenic
0.95
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D;D
MetaSVM
Pathogenic
0.90
D
MutationAssessor
Pathogenic
4.1
H;.;.;H;.;H
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.90
D
PROVEAN
Pathogenic
-7.0
D;.;.;D;.;.
REVEL
Pathogenic
0.82
Sift
Uncertain
0.0010
D;.;.;D;.;.
Sift4G
Uncertain
0.0030
D;.;.;D;D;D
Polyphen
1.0
D;.;.;D;.;.
Vest4
0.99
MutPred
0.96
Loss of stability (P = 0.0566);Loss of stability (P = 0.0566);Loss of stability (P = 0.0566);Loss of stability (P = 0.0566);Loss of stability (P = 0.0566);Loss of stability (P = 0.0566);
MVP
0.99
MPC
2.9
ClinPred
1.0
D
GERP RS
6.2
Varity_R
0.99
gMVP
1.0

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs267608500; hg19: chrX-18606097; API