chr11-116857914-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_001366686.3(SIK3):ā€‹c.3551C>Gā€‹(p.Pro1184Arg) variant causes a missense change. The variant allele was found at a frequency of 0.179 in 1,613,960 control chromosomes in the GnomAD database, including 26,821 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.17 ( 2320 hom., cov: 32)
Exomes š‘“: 0.18 ( 24501 hom. )

Consequence

SIK3
NM_001366686.3 missense

Scores

1
7
8

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 5.16
Variant links:
Genes affected
SIK3 (HGNC:29165): (SIK family kinase 3) Enables ATP binding activity; magnesium ion binding activity; and protein serine/threonine kinase activity. Involved in positive regulation of TORC1 signaling; positive regulation of TORC2 signaling; and protein phosphorylation. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SIK3. . Trascript score misZ 3.9277 (greater than threshold 3.09). GenCC has associacion of gene with spondyloepimetaphyseal dysplasia, Krakow type.
BP4
Computational evidence support a benign effect (MetaRNN=0.0016655326).
BP6
Variant 11-116857914-G-C is Benign according to our data. Variant chr11-116857914-G-C is described in ClinVar as [Benign]. Clinvar id is 1332964.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.249 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SIK3NM_001366686.3 linkuse as main transcriptc.3551C>G p.Pro1184Arg missense_variant 21/25 ENST00000445177.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SIK3ENST00000445177.6 linkuse as main transcriptc.3551C>G p.Pro1184Arg missense_variant 21/255 NM_001366686.3 A2

Frequencies

GnomAD3 genomes
AF:
0.170
AC:
25891
AN:
151984
Hom.:
2312
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.143
Gnomad AMI
AF:
0.138
Gnomad AMR
AF:
0.186
Gnomad ASJ
AF:
0.153
Gnomad EAS
AF:
0.0938
Gnomad SAS
AF:
0.260
Gnomad FIN
AF:
0.192
Gnomad MID
AF:
0.171
Gnomad NFE
AF:
0.181
Gnomad OTH
AF:
0.166
GnomAD3 exomes
AF:
0.188
AC:
47169
AN:
251452
Hom.:
4709
AF XY:
0.190
AC XY:
25778
AN XY:
135894
show subpopulations
Gnomad AFR exome
AF:
0.144
Gnomad AMR exome
AF:
0.230
Gnomad ASJ exome
AF:
0.164
Gnomad EAS exome
AF:
0.0943
Gnomad SAS exome
AF:
0.256
Gnomad FIN exome
AF:
0.192
Gnomad NFE exome
AF:
0.179
Gnomad OTH exome
AF:
0.183
GnomAD4 exome
AF:
0.180
AC:
262609
AN:
1461858
Hom.:
24501
Cov.:
33
AF XY:
0.182
AC XY:
132296
AN XY:
727230
show subpopulations
Gnomad4 AFR exome
AF:
0.141
Gnomad4 AMR exome
AF:
0.223
Gnomad4 ASJ exome
AF:
0.165
Gnomad4 EAS exome
AF:
0.0904
Gnomad4 SAS exome
AF:
0.256
Gnomad4 FIN exome
AF:
0.193
Gnomad4 NFE exome
AF:
0.176
Gnomad4 OTH exome
AF:
0.172
GnomAD4 genome
AF:
0.171
AC:
25936
AN:
152102
Hom.:
2320
Cov.:
32
AF XY:
0.172
AC XY:
12824
AN XY:
74366
show subpopulations
Gnomad4 AFR
AF:
0.143
Gnomad4 AMR
AF:
0.186
Gnomad4 ASJ
AF:
0.153
Gnomad4 EAS
AF:
0.0940
Gnomad4 SAS
AF:
0.261
Gnomad4 FIN
AF:
0.192
Gnomad4 NFE
AF:
0.181
Gnomad4 OTH
AF:
0.165
Alfa
AF:
0.161
Hom.:
1340
Bravo
AF:
0.167
TwinsUK
AF:
0.186
AC:
688
ALSPAC
AF:
0.177
AC:
684
ESP6500AA
AF:
0.137
AC:
603
ESP6500EA
AF:
0.173
AC:
1488
ExAC
AF:
0.187
AC:
22701
Asia WGS
AF:
0.191
AC:
661
AN:
3478
EpiCase
AF:
0.180
EpiControl
AF:
0.176

ClinVar

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

Submissions by phenotype

SIK3-related disorder Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesOct 21, 2019This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Spondyloepimetaphyseal dysplasia, Krakow type Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabJul 15, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.40
T
BayesDel_noAF
Benign
-0.20
CADD
Pathogenic
26
DANN
Uncertain
0.99
Eigen
Uncertain
0.31
Eigen_PC
Uncertain
0.38
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.92
D;D
MetaRNN
Benign
0.0017
T;T
MetaSVM
Benign
-1.1
T
MutationTaster
Benign
0.0021
P;P;P;P;P;P
PrimateAI
Uncertain
0.54
T
PROVEAN
Benign
-2.1
N;N
REVEL
Benign
0.14
Sift
Uncertain
0.0020
D;D
Sift4G
Uncertain
0.038
D;D
Vest4
0.53
ClinPred
0.034
T
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.18
gMVP
0.47

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs12225230; hg19: chr11-116728630; COSMIC: COSV52610990; COSMIC: COSV52610990; API