21-43416836-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

Genomes: not found (cov: 0)

Consequence

SIK1
NM_173354.5 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.52

Publications

0 publications found
Variant links:
Genes affected
SIK1 (HGNC:11142): (salt inducible kinase 1) This gene encodes a serine/threonine protein kinase that contains a ubiquitin-associated (UBA) domain. The encoded protein is a member of the adenosine monophosphate-activated kinase (AMPK) subfamily of kinases that play a role in conserved signal transduction pathways. A mutation in this gene is associated with early infantile epileptic encephalopathy 30. [provided by RefSeq, Nov 2016]
SIK1 Gene-Disease associations (from GenCC):
  • developmental and epileptic encephalopathy, 30
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
  • early myoclonic encephalopathy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • genetic developmental and epileptic encephalopathy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • infantile spasms
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • generalized epilepsy
    Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.12131256).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SIK1NM_173354.5 linkc.2258C>T p.Ala753Val missense_variant Exon 14 of 14 ENST00000270162.8 NP_775490.2 P57059
SIK1XM_011529474.3 linkc.2111C>T p.Ala704Val missense_variant Exon 13 of 13 XP_011527776.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SIK1ENST00000270162.8 linkc.2258C>T p.Ala753Val missense_variant Exon 14 of 14 1 NM_173354.5 ENSP00000270162.6 P57059

Frequencies

GnomAD3 genomes
Cov.:
0
GnomAD2 exomes
AF:
0.0000210
AC:
5
AN:
238546
AF XY:
0.0000153
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000147
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Cov.:
0
GnomAD4 genome
Cov.:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 30 Uncertain:1
Aug 23, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.085
BayesDel_addAF
Benign
-0.31
T
BayesDel_noAF
Benign
-0.43
CADD
Benign
17
DANN
Uncertain
0.99
DEOGEN2
Benign
0.11
T
Eigen
Benign
-0.28
Eigen_PC
Benign
-0.13
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Benign
0.51
T
M_CAP
Benign
0.039
D
MetaRNN
Benign
0.12
T
MetaSVM
Benign
-0.83
T
MutationAssessor
Benign
0.69
N
PhyloP100
3.5
PrimateAI
Uncertain
0.54
T
PROVEAN
Benign
-1.1
N
REVEL
Benign
0.10
Sift
Benign
0.031
D
Sift4G
Benign
0.15
T
Polyphen
0.085
B
Vest4
0.048
MutPred
0.19
Loss of disorder (P = 0.0552);
MVP
0.42
MPC
0.17
ClinPred
0.15
T
GERP RS
4.9
Varity_R
0.10
gMVP
0.39
Mutation Taster
=96/4
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs1444363139; hg19: chr21-44836716; API