11-116857914-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001366686.3(SIK3):c.3551C>G(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 (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2320 hom., cov: 32)
  • Exomes 𝑓: 0.18 (24501 hom.)
• Consequence: SIK3 NM_001366686.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.16

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SIK3
• 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
SIK3	NM_001366686.3	c.3551C>G	p.Pro1184Arg	missense_variant	21/25	ENST00000445177.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIK3	ENST00000445177.6	c.3551C>G	p.Pro1184Arg	missense_variant	21/25	5	NM_001366686.3	A2

Frequencies

GnomAD3 genomes AF: 0.170 AC: 25891 AN: 151984 Hom.: 2312 Cov.: 32

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

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

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

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

Submissions by phenotype

SIK3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2019

This 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 submitter

clinical testing

Genome-Nilou Lab

Jul 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

Other links and lift over

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