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
Consequence
ENST00000623535.2 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CDKL5 | NM_001323289.2 | c.578A>G | p.Asp193Gly | missense_variant | 9/18 | ENST00000623535.2 | NP_001310218.1 | |
CDKL5 | NM_001037343.2 | c.578A>G | p.Asp193Gly | missense_variant | 10/22 | NP_001032420.1 | ||
CDKL5 | NM_003159.3 | c.578A>G | p.Asp193Gly | missense_variant | 9/21 | NP_003150.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CDKL5 | ENST00000623535.2 | c.578A>G | p.Asp193Gly | missense_variant | 9/18 | 1 | NM_001323289.2 | ENSP00000485244 | P1 |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD4 exome AF: 9.11e-7 AC: 1AN: 1097378Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 1AN XY: 362786
GnomAD4 genome Cov.: 23
ClinVar
Submissions by phenotype
Developmental and epileptic encephalopathy, 2 Pathogenic:2
Pathogenic, no assertion criteria provided | curation | RettBASE | Mar 13, 2014 | Mutation 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 submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
CDKL5 disorder Pathogenic:2
Likely pathogenic, criteria provided, single submitter | curation | Centre for Population Genomics, CPG | Jul 11, 2024 | 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 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 panel | curation | ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel | Mar 26, 2021 | 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). - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at