chr21-43416836-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.2258C>T(p.Ala753Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign 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. A753S) has been classified as Likely 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 Cov.: 0
GnomAD2 exomes AF: 0.0000210 AC: 5AN: 238546 AF XY: 0.0000153 show subpopulations
GnomAD4 exome Cov.: 0
GnomAD4 genome Cov.: 0
ClinVar
Submissions by phenotype
Developmental and epileptic encephalopathy, 30 Uncertain:1
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SIK1 protein function. ClinVar contains an entry for this variant (Variation ID: 1500908). This variant has not been reported in the literature in individuals affected with SIK1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.02%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 753 of the SIK1 protein (p.Ala753Val). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at