rs746408860
Positions:
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The NM_173354.5(SIK1):c.1219T>C(p.Cys407Arg) 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
NM_173354.5 missense
Scores
9
10
Clinical Significance
Conservation
PhyloP100: 3.61
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=0.39975363).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SIK1 | NM_173354.5 | c.1219T>C | p.Cys407Arg | missense_variant | 10/14 | ENST00000270162.8 | |
SIK1 | XM_011529474.3 | c.1072T>C | p.Cys358Arg | missense_variant | 9/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SIK1 | ENST00000270162.8 | c.1219T>C | p.Cys407Arg | missense_variant | 10/14 | 1 | NM_173354.5 | P1 | |
SIK1 | ENST00000644871.1 | n.164T>C | non_coding_transcript_exon_variant | 2/2 |
Frequencies
GnomAD3 genomes ? Cov.: 0
GnomAD3 genomes
?
Cov.:
0
GnomAD3 exomes AF: 0.00000803 AC: 2AN: 249002Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135188
GnomAD3 exomes
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2
AN:
249002
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AC XY:
2
AN XY:
135188
Gnomad AFR exome
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GnomAD4 exome Cov.: 0
GnomAD4 exome
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0
GnomAD4 genome ? Cov.: 0
GnomAD4 genome
?
Cov.:
0
Alfa
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ExAC
?
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1
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 20, 2019 | - - |
Developmental and epileptic encephalopathy, 30 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 05, 2022 | This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 407 of the SIK1 protein (p.Cys407Arg). This variant is present in population databases (rs746408860, gnomAD 0.007%). 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: 542708). This variant has not been reported in the literature in individuals affected with SIK1-related conditions. - |
Seizure Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | New York Genome Center | Oct 30, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
LIST_S2
Benign
T
M_CAP
Uncertain
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Benign
Sift
Uncertain
D
Sift4G
Benign
T
Polyphen
P
Vest4
MutPred
Gain of disorder (P = 0.1105);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
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