rs141478957
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_001323289.2(CDKL5):āc.1797C>Gā(p.Thr599=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000746 in 1,210,102 control chromosomes in the GnomAD database, including 4 homozygotes. There are 260 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (ā ā ).
Frequency
Genomes: š 0.0042 ( 3 hom., 136 hem., cov: 23)
Exomes š: 0.00040 ( 1 hom. 124 hem. )
Consequence
CDKL5
NM_001323289.2 synonymous
NM_001323289.2 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.712
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 Benign. Variant got -21 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.5).
BP6
?
Variant X-18604721-C-G is Benign according to our data. Variant chrX-18604721-C-G is described in ClinVar as [Benign]. Clinvar id is 94106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
Synonymous conserved (PhyloP=0.712 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00417 (468/112156) while in subpopulation AFR AF= 0.0136 (421/30855). AF 95% confidence interval is 0.0126. There are 3 homozygotes in gnomad4. There are 136 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd4 at 3 XL gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDKL5 | NM_001323289.2 | c.1797C>G | p.Thr599= | synonymous_variant | 12/18 | ENST00000623535.2 | |
CDKL5 | NM_001037343.2 | c.1797C>G | p.Thr599= | synonymous_variant | 13/22 | ||
CDKL5 | NM_003159.3 | c.1797C>G | p.Thr599= | synonymous_variant | 12/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDKL5 | ENST00000623535.2 | c.1797C>G | p.Thr599= | synonymous_variant | 12/18 | 1 | NM_001323289.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00417 AC: 468AN: 112101Hom.: 3 Cov.: 23 AF XY: 0.00400 AC XY: 137AN XY: 34283
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GnomAD3 exomes AF: 0.00110 AC: 202AN: 183227Hom.: 2 AF XY: 0.000783 AC XY: 53AN XY: 67731
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GnomAD4 exome AF: 0.000396 AC: 435AN: 1097946Hom.: 1 Cov.: 32 AF XY: 0.000341 AC XY: 124AN XY: 363304
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GnomAD4 genome ? AF: 0.00417 AC: 468AN: 112156Hom.: 3 Cov.: 23 AF XY: 0.00396 AC XY: 136AN XY: 34348
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ClinVar
Significance: Benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 23, 2013 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 04, 2013 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 26, 2018 | - - |
CDKL5-related disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 07, 2023 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
History of neurodevelopmental disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 07, 2016 | General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance - |
Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at