rs774841964
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3PP5
The NM_015443.4(KANSL1):c.1774C>T(p.Arg592Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R592Q) has been classified as Likely pathogenic.
Frequency
Consequence
NM_015443.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KANSL1 | NM_015443.4 | c.1774C>T | p.Arg592Trp | missense_variant | 6/15 | ENST00000432791.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KANSL1 | ENST00000432791.7 | c.1774C>T | p.Arg592Trp | missense_variant | 6/15 | 1 | NM_015443.4 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 30, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variant in a gene in which most reported pathogenic variants are truncating/loss-of-function; This variant is associated with the following publications: (PMID: 36150256, 31273778) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratoire Génétique Moléculaire, CHRU TOURS | Apr 06, 2020 | - - |
Koolen-de Vries syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 01, 2017 | This variant has been shown to arise de novo in individuals affected with a seizure disorder (Invitae). However, previously reported disease-causing de novo variants in KANSL1 have been truncations or gene deletions (PMID: 2544363, 26424144, 22544367, 26306646). In summary, this variant has been observed to arise de novo in a single individual. In the absence of additional clinical or functional data, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with tryptophan at codon 592 of the KANSL1 protein (p.Arg592Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 19, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at