chr21-43418400-G-A
Variant summary
Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_173354.5(SIK1):c.1604C>T(p.Pro535Leu) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P535P) has been classified as Benign.
Frequency
Consequence
NM_173354.5 missense
Scores
Clinical Significance
Conservation
Publications
- developmental and epileptic encephalopathy, 30Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
- early myoclonic encephalopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- genetic developmental and epileptic encephalopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- infantile spasmsInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- generalized epilepsyInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
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ACMG classification
Our verdict: Likely_benign. The variant received -2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00 AC: 0AN: 66Hom.: 0 Cov.: 0
GnomAD2 exomes AF: 0.0000125 AC: 3AN: 240002 AF XY: 0.0000152 show subpopulations
GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 13644Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0AN XY: 6854
GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 66Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0AN XY: 48
ClinVar
Submissions by phenotype
Developmental and epileptic encephalopathy, 30 Uncertain:2
In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is present in population databases (rs373576665, ExAC 0.002%) but has not been reported in the literature in individuals with a SIK1-related disease. This sequence change replaces proline with leucine at codon 535 of the SIK1 protein (p.Pro535Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at