11-116857914-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 5.16

Publications

49 publications found

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]

SIK3 Gene-Disease associations (from GenCC):

autism
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
hearing loss disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
spondyloepimetaphyseal dysplasia, Krakow type
Inheritance: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

SIK3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

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 rank	MANE	Protein	UniProt
SIK3	NM_001366686.3 link	c.3551C>G	p.Pro1184Arg	missense_variant	Exon 21 of 25	ENST00000445177.6	NP_001353615.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIK3	ENST00000445177.6 link	c.3551C>G	p.Pro1184Arg	missense_variant	Exon 21 of 25	5	NM_001366686.3	ENSP00000391295.2		H0Y4E8

Frequencies

GnomAD3 genomes

AF:

0.170

AC:

25891

AN:

151984

Hom.:

2312

Cov.:

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

GnomAD2 exomes

AF:

0.188

AC:

47169

AN:

251452

AF XY:

0.190

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 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.:

AF XY:

0.182

AC XY:

132296

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.141

AC:

4718

AN:

33480

American (AMR)

AF:

0.223

AC:

9995

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.165

AC:

4312

AN:

26136

East Asian (EAS)

AF:

0.0904

AC:

3587

AN:

39700

South Asian (SAS)

AF:

0.256

AC:

22091

AN:

86256

European-Finnish (FIN)

AF:

0.193

AC:

10305

AN:

53418

Middle Eastern (MID)

AF:

0.171

AC:

985

AN:

5768

European-Non Finnish (NFE)

AF:

0.176

AC:

196240

AN:

1111980

Other (OTH)

AF:

0.172

AC:

10376

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

13992

27984

41976

55968

69960

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.171

AC:

25936

AN:

152102

Hom.:

2320

Cov.:

AF XY:

0.172

AC XY:

12824

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.143

AC:

5944

AN:

41478

American (AMR)

AF:

0.186

AC:

2834

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.153

AC:

532

AN:

3468

East Asian (EAS)

AF:

0.0940

AC:

486

AN:

5168

South Asian (SAS)

AF:

0.261

AC:

1255

AN:

4810

European-Finnish (FIN)

AF:

0.192

AC:

2030

AN:

10582

Middle Eastern (MID)

AF:

0.170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.181

AC:

12330

AN:

68004

Other (OTH)

AF:

0.165

AC:

349

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1100

2200

3300

4400

5500

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

SIK3-related disorder

Benign:1

Oct 21, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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). -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Spondyloepimetaphyseal dysplasia, Krakow type

Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

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

-0.40

BayesDel_noAF

Benign

-0.20

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.92

D;D

MetaRNN

Benign

0.0017

T;T

MetaSVM

Benign

-1.1

PhyloP100

5.2

PrimateAI

Uncertain

0.54

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

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.18

gMVP

0.47

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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11-116857914-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over