chrX-18650520-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 8P and 8B. PVS1BP6_Very_Strong
The ENST00000379989.6(CDKL5):c.2908C>T(p.Arg970Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,210,465 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
ENST00000379989.6 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RS1 | NM_000330.4 | c.185-3188G>A | intron_variant | ENST00000379984.4 | |||
CDKL5 | NM_001037343.2 | c.2908C>T | p.Arg970Ter | stop_gained | 21/22 | ||
CDKL5 | NM_003159.3 | c.2908C>T | p.Arg970Ter | stop_gained | 20/21 | ||
RS1 | XM_047442337.1 | c.-137G>A | 5_prime_UTR_variant | 1/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RS1 | ENST00000379984.4 | c.185-3188G>A | intron_variant | 1 | NM_000330.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000178 AC: 2AN: 112511Hom.: 0 Cov.: 23 AF XY: 0.0000288 AC XY: 1AN XY: 34681
GnomAD3 exomes AF: 0.0000109 AC: 2AN: 183458Hom.: 0 AF XY: 0.0000147 AC XY: 1AN XY: 67886
GnomAD4 exome AF: 0.0000255 AC: 28AN: 1097954Hom.: 0 Cov.: 30 AF XY: 0.0000248 AC XY: 9AN XY: 363314
GnomAD4 genome ? AF: 0.0000178 AC: 2AN: 112511Hom.: 0 Cov.: 23 AF XY: 0.0000288 AC XY: 1AN XY: 34681
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | Jun 02, 2023 | - - |
Atypical Rett syndrome Uncertain:1
Uncertain significance, no assertion criteria provided | curation | RettBASE | Mar 13, 2014 | In exon 20, affecting only the transcript lowly expressed - |
CDKL5 disorder Benign:1
Benign, reviewed by expert panel | curation | ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel | Dec 06, 2023 | RS1(NM_000330.4) and an alternative transcript of CDKL5 (NM_003159.2) are overlapping transcripts; however, these variants are in the noncoding 3' region of the main CDKL5 transcript (NM_001323289.2). The allele frequency of the c.2908C>T (p.Arg970Ter) variant in CDKL5 transcript (NM_003159.2) is 0.02285% in the Middle Eastern sub population in gnomAD v4, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Arg970Ter variant in CDKL5 has been reported in an individual with a clinical phenotype suggestive of CDKL5 disorder (PMID 19428276), however this criterion cannot be applied due the allele frequency of the variant in gnomAD (PP4 not met). The p.Arg970Ter is observed in at least 5 unaffected individuals (internal database - GeneDx). In summary, the p.Arg970Ter variant in CDKL5 is classified as Benign based on the ACMG/AMP criteria (BS1, BS2). - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 23, 2021 | This variant is associated with the following publications: (PMID: 22670135, 25525159, 19428276, 23756444) - |
Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Nov 24, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at