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

Genomes: 𝑓 0.0 ( 0 hom., cov: 0)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

SIK1
NM_173354.5 missense

Scores

7
12

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.91

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=0.21333057).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SIK1NM_173354.5 linkc.1604C>T p.Pro535Leu missense_variant Exon 12 of 14 ENST00000270162.8 NP_775490.2 P57059
SIK1XM_011529474.3 linkc.1457C>T p.Pro486Leu missense_variant Exon 11 of 13 XP_011527776.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SIK1ENST00000270162.8 linkc.1604C>T p.Pro535Leu missense_variant Exon 12 of 14 1 NM_173354.5 ENSP00000270162.6 P57059

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
0
AN:
66
Hom.:
0
Cov.:
0
Gnomad AFR
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000125
AC:
3
AN:
240002
AF XY:
0.0000152
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000284
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AC0;AS_VQSR
AF:
0.00
AC:
0
AN:
13644
Hom.:
0
Cov.:
0
AF XY:
0.00
AC XY:
0
AN XY:
6854
African (AFR)
AF:
0.00
AC:
0
AN:
1370
American (AMR)
AF:
0.00
AC:
0
AN:
378
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
746
East Asian (EAS)
AF:
0.00
AC:
0
AN:
750
South Asian (SAS)
AF:
0.00
AC:
0
AN:
414
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
536
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
130
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
8278
Other (OTH)
AF:
0.00
AC:
0
AN:
1042
GnomAD4 genome
Data not reliable, filtered out with message: AC0;AS_VQSR
AF:
0.00
AC:
0
AN:
66
Hom.:
0
Cov.:
0
AF XY:
0.00
AC XY:
0
AN XY:
48
African (AFR)
AF:
0.00
AC:
0
AN:
30
American (AMR)
AF:
0.00
AC:
0
AN:
8
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
6
East Asian (EAS)
AF:
0.00
AC:
0
AN:
2
South Asian (SAS)
AF:
0.00
AC:
0
AN:
2
European-Finnish (FIN)
AC:
0
AN:
0
Middle Eastern (MID)
AC:
0
AN:
0
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
14
Other (OTH)
AF:
0.00
AC:
0
AN:
4
Alfa
AF:
0.0000283
Hom.:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.00000826
AC:
1
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 30 Uncertain:2
Apr 01, 2017
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. -

Aug 25, 2022
Revvity Omics, Revvity
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Benign
-0.39
CADD
Benign
22
DANN
Benign
0.93
DEOGEN2
Uncertain
0.47
T
Eigen
Benign
-0.37
Eigen_PC
Benign
-0.34
FATHMM_MKL
Uncertain
0.80
D
LIST_S2
Benign
0.79
T
M_CAP
Benign
0.052
D
MetaRNN
Benign
0.21
T
MetaSVM
Benign
-0.79
T
MutationAssessor
Uncertain
2.1
M
PhyloP100
5.9
PrimateAI
Uncertain
0.52
T
PROVEAN
Uncertain
-4.1
D
REVEL
Benign
0.17
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.055
T
Polyphen
0.026
B
Vest4
0.27
MVP
0.30
MPC
0.62
ClinPred
0.42
T
GERP RS
2.8
Varity_R
0.14
gMVP
0.38
Mutation Taster
=95/5
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: rs373576665; hg19: chr21-44838280; API