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GeneBe

21-43416792-T-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_173354.5(SIK1):c.2302A>G(p.Met768Val) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 0)

Consequence

SIK1
NM_173354.5 missense

Scores

1
8
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.65
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.2819624).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SIK1NM_173354.5 linkuse as main transcriptc.2302A>G p.Met768Val missense_variant 14/14 ENST00000270162.8
SIK1XM_011529474.3 linkuse as main transcriptc.2155A>G p.Met719Val missense_variant 13/13

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SIK1ENST00000270162.8 linkuse as main transcriptc.2302A>G p.Met768Val missense_variant 14/141 NM_173354.5 P1

Frequencies

GnomAD3 genomes
Cov.:
0
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
Uncertain significance, criteria provided, single submitterclinical testingInvitaeJun 14, 2022In 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. This variant has not been reported in the literature in individuals affected with SIK1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 768 of the SIK1 protein (p.Met768Val). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Uncertain
-0.080
Cadd
Benign
22
Dann
Uncertain
1.0
DEOGEN2
Benign
0.14
T
Eigen
Uncertain
0.20
Eigen_PC
Uncertain
0.29
FATHMM_MKL
Uncertain
0.81
D
LIST_S2
Benign
0.81
T
M_CAP
Benign
0.057
D
MetaRNN
Benign
0.28
T
MetaSVM
Benign
-0.33
T
MutationAssessor
Benign
1.9
L
MutationTaster
Benign
0.51
D
PrimateAI
Uncertain
0.74
T
PROVEAN
Benign
-1.6
N
REVEL
Benign
0.27
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.022
D
Polyphen
0.82
P
Vest4
0.46
MutPred
0.32
Gain of catalytic residue at M768 (P = 0.0295);
MVP
0.59
MPC
0.14
ClinPred
0.72
D
GERP RS
5.1
Varity_R
0.81
gMVP
0.59

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-44836672; API