17-46066611-G-C
Position:
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM5PP3
The NM_015443.4(KANSL1):c.1774C>G(p.Arg592Gly) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R592Q) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
KANSL1
NM_015443.4 missense
NM_015443.4 missense
Scores
6
9
1
Clinical Significance
Conservation
PhyloP100: 4.04
Genes affected
KANSL1 (HGNC:24565): (KAT8 regulatory NSL complex subunit 1) This gene encodes a nuclear protein that is a subunit of two protein complexes involved with histone acetylation, the MLL1 complex and the NSL1 complex. The encoded protein has been implicated in a variety of cellular processes including enhancer regulation, cell proliferation, and mitosis. Mutations in this gene are associated with Koolen-de Vries Syndrome. [provided by RefSeq, May 2022]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-46066610-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2505885.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.799
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KANSL1 | NM_015443.4 | c.1774C>G | p.Arg592Gly | missense_variant | 6/15 | ENST00000432791.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KANSL1 | ENST00000432791.7 | c.1774C>G | p.Arg592Gly | missense_variant | 6/15 | 1 | NM_015443.4 | P4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 18, 2017 | The R592G variant in the KANSL1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R592G variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R592G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R592G as a variant of uncertain significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
T
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.;.;.;.;D;.;.;.;.
REVEL
Uncertain
Sift
Pathogenic
D;.;.;.;.;D;.;.;.;.
Sift4G
Uncertain
D;D;D;.;D;D;.;.;.;.
Vest4
MutPred
Loss of MoRF binding (P = 0.0355);Loss of MoRF binding (P = 0.0355);Loss of MoRF binding (P = 0.0355);Loss of MoRF binding (P = 0.0355);Loss of MoRF binding (P = 0.0355);Loss of MoRF binding (P = 0.0355);Loss of MoRF binding (P = 0.0355);Loss of MoRF binding (P = 0.0355);.;Loss of MoRF binding (P = 0.0355);
MVP
MPC
1.5
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at