rs866859766
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP3BP6_Very_StrongBS2
The ENST00000379989.6(CDKL5):c.2980G>A(p.Gly994Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,097,473 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G994A) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000379989.6 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RS1 | NM_000330.4 | c.185-3260C>T | intron_variant | ENST00000379984.4 | |||
CDKL5 | NM_001037343.2 | c.2980G>A | p.Gly994Arg | missense_variant, splice_region_variant | 21/22 | ||
CDKL5 | NM_003159.3 | c.2980G>A | p.Gly994Arg | missense_variant, splice_region_variant | 20/21 | ||
RS1 | XM_047442337.1 | c.-209C>T | 5_prime_UTR_variant | 1/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDKL5 | ENST00000379989.6 | c.2980G>A | p.Gly994Arg | missense_variant, splice_region_variant | 21/22 | 1 | |||
CDKL5 | ENST00000379996.7 | c.2980G>A | p.Gly994Arg | missense_variant, splice_region_variant | 20/21 | 1 | |||
RS1 | ENST00000379984.4 | c.185-3260C>T | intron_variant | 1 | NM_000330.4 | P1 | |||
CDKL5 | ENST00000673617.1 | n.252G>A | splice_region_variant, non_coding_transcript_exon_variant | 2/3 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD3 exomes AF: 0.00000547 AC: 1AN: 182807Hom.: 0 AF XY: 0.0000149 AC XY: 1AN XY: 67319
GnomAD4 exome AF: 0.0000164 AC: 18AN: 1097473Hom.: 0 Cov.: 30 AF XY: 0.00000827 AC XY: 3AN XY: 362841
GnomAD4 genome ? Cov.: 23
ClinVar
Submissions by phenotype
Epileptic encephalopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Neurogenetics Laboratory - MEYER, AOU Meyer | Nov 16, 2016 | - - |
CDKL5 disorder Benign:1
Likely benign, reviewed by expert panel | curation | ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel | Feb 20, 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 c.2980G>A (p.Gly994Arg) variant in CDKL5 transcript (NM_003159.2) (RS1 c.185-3260C>T) is present in 0 female/1 male individual in gnomAD v2.1.1 (0.001227%) (not sufficient to meet BS1 criteria). Computational analysis prediction tools suggest that the p.Gly994Arg variant in CDKL5 does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). The p.Gly994Arg variant in CDKL5 is observed in at least 1 unaffected individual (PMID 29264392) (BS2_Supporting). In summary, the p.Gly994Arg in CDKL5 is classified as likely benign based on the ACMG/AMP criteria (BS2_Supporting, BP4). - |
Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Dec 18, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at