rs756986206
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP7BS2_SupportingBA1
This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Ala334= variant in CDKL5 is 0.07448% in South Asian sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Ala334= variant is observed in at least 1 unaffected individual (Clinvar 210642) (BS2_supporting). The silent p.Ala334= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). In summary, the p.Ala334= variant in CDKL5 is classified as Benign based on the ACMG/AMP criteria (BA1, BA2_supporting, BP7). LINK:https://erepo.genome.network/evrepo/ui/classification/CA207213/MONDO:0100039/016
Frequency
Consequence
NM_001323289.2 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDKL5 | NM_001323289.2 | c.1002T>C | p.Ala334= | synonymous_variant | 12/18 | ENST00000623535.2 | |
CDKL5 | NM_001037343.2 | c.1002T>C | p.Ala334= | synonymous_variant | 13/22 | ||
CDKL5 | NM_003159.3 | c.1002T>C | p.Ala334= | synonymous_variant | 12/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDKL5 | ENST00000623535.2 | c.1002T>C | p.Ala334= | synonymous_variant | 12/18 | 1 | NM_001323289.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000447 AC: 5AN: 111918Hom.: 0 Cov.: 23 AF XY: 0.0000881 AC XY: 3AN XY: 34066
GnomAD3 exomes AF: 0.000109 AC: 20AN: 183298Hom.: 0 AF XY: 0.000133 AC XY: 9AN XY: 67772
GnomAD4 exome AF: 0.000107 AC: 117AN: 1097142Hom.: 2 Cov.: 31 AF XY: 0.000119 AC XY: 43AN XY: 362516
GnomAD4 genome ? AF: 0.0000447 AC: 5AN: 111970Hom.: 0 Cov.: 23 AF XY: 0.0000879 AC XY: 3AN XY: 34128
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | CDKL5: BP4, BP7, BS2 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 22, 2015 | - - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 31, 2018 | - - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 10, 2016 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
CDKL5 disorder Benign:1
Benign, reviewed by expert panel | curation | ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel | Feb 20, 2023 | The allele frequency of the p.Ala334= variant in CDKL5 is 0.07448% in South Asian sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Ala334= variant is observed in at least 1 unaffected individual (Clinvar 210642) (BS2_supporting). The silent p.Ala334= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). In summary, the p.Ala334= variant in CDKL5 is classified as Benign based on the ACMG/AMP criteria (BA1, BA2_supporting, BP7). - |
CDKL5-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 08, 2019 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at