rs144878564
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_001323289.2(CDKL5):c.1892T>C(p.Ile631Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000248 in 1,209,621 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I631V) has been classified as Uncertain significance.
Frequency
Consequence
NM_001323289.2 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDKL5 | NM_001323289.2 | c.1892T>C | p.Ile631Thr | missense_variant | 12/18 | ENST00000623535.2 | |
CDKL5 | NM_001037343.2 | c.1892T>C | p.Ile631Thr | missense_variant | 13/22 | ||
CDKL5 | NM_003159.3 | c.1892T>C | p.Ile631Thr | missense_variant | 12/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDKL5 | ENST00000623535.2 | c.1892T>C | p.Ile631Thr | missense_variant | 12/18 | 1 | NM_001323289.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000108 AC: 12AN: 111619Hom.: 0 Cov.: 23 AF XY: 0.0000887 AC XY: 3AN XY: 33825
GnomAD3 exomes AF: 0.0000328 AC: 6AN: 182969Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 67535
GnomAD4 exome AF: 0.0000164 AC: 18AN: 1098002Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 5AN XY: 363358
GnomAD4 genome ? AF: 0.000108 AC: 12AN: 111619Hom.: 0 Cov.: 23 AF XY: 0.0000887 AC XY: 3AN XY: 33825
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 09, 2015 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 13, 2020 | This variant is associated with the following publications: (PMID: 19793311) - |
Developmental and epileptic encephalopathy, 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 02, 2017 | The p.I631T variant (also known as c.1892T>C), located in coding exon 11 of the CDKL5 gene, results from a T to C substitution at nucleotide position 1892. The isoleucine at codon 631 is replaced by threonine, an amino acid with similar properties. This alteration was detected as maternally inherited in an individual with early onset seizures (Nemos C et al. Clin. Genet., 2009 Oct;76:357-71). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 19, 2023 | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 631 of the CDKL5 protein (p.Ile631Thr). This variant is present in population databases (rs144878564, gnomAD 0.02%). This missense change has been observed in individual(s) with seizures (PMID: 19793311). ClinVar contains an entry for this variant (Variation ID: 143786). 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 not expected to disrupt CDKL5 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not specified Benign:1
Likely benign, no assertion criteria provided | curation | RettBASE | May 09, 2014 | Identified in unaffect female with random X-inactivation pattern; in silico predictions: SIFT = tolerated, MutationTaster = polymorphism, PolyPhen2 = benign, AlignGVGD = benign (C0) - |
CDKL5 disorder Benign:1
Benign, reviewed by expert panel | curation | ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel | Aug 25, 2022 | The allele frequency of the p.Ile631Thr variant in CDKL5 is 0.03% in African 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.Ile631Thr variant is observed in at least 2 unaffected individuals (internal database) (BS2). The p.Ile631Thr variant is observed in the CDKL5 gene where a second pathogenic variant in the same gene is present in the patient (PMID 19793311) (BP2). In summary, the p.Ile631Thr variant in CDKL5 is classified as benign based on the ACMG/AMP criteria (BA1, BS2, BP2). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at