11-116858197-G-A

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.3268C>T(p.Arg1090Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00497 in 1,614,080 control chromosomes in the GnomAD database, including 288 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (155 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (133 hom.)
• Consequence: SIK3 NM_001366686.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.94

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=0.0017143786).
• BP6: Variant 11-116858197-G-A is Benign according to our data. Variant chr11-116858197-G-A is described in ClinVar as [Benign]. Clinvar id is 776662.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0873 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIK3	NM_001366686.3	c.3268C>T	p.Arg1090Cys	missense_variant	21/25	ENST00000445177.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIK3	ENST00000445177.6	c.3268C>T	p.Arg1090Cys	missense_variant	21/25	5	NM_001366686.3	A2

Frequencies

GnomAD3 genomes AF: 0.0258 AC: 3923 AN: 152070 Hom.: 155 Cov.: 32

Gnomad AFR AF: 0.0900

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00930

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.0172

GnomAD3 exomes AF: 0.00651 AC: 1636 AN: 251182 Hom.: 54 AF XY: 0.00448 AC XY: 608 AN XY: 135746

Gnomad AFR exome AF: 0.0904

Gnomad AMR exome AF: 0.00356

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000203

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00280 AC: 4090 AN: 1461892 Hom.: 133 Cov.: 32 AF XY: 0.00240 AC XY: 1747 AN XY: 727248

Gnomad4 AFR exome AF: 0.0947

Gnomad4 AMR exome AF: 0.00470

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000255

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000306

Gnomad4 OTH exome AF: 0.00533

GnomAD4 genome AF: 0.0258 AC: 3924 AN: 152188 Hom.: 155 Cov.: 32 AF XY: 0.0247 AC XY: 1835 AN XY: 74416

Gnomad4 AFR AF: 0.0897

Gnomad4 AMR AF: 0.00929

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.00528 Hom.: 59

Bravo AF: 0.0294

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0891 AC: 392

ESP6500EA AF: 0.000466 AC: 4

ExAC AF: 0.00777 AC: 943

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000356

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

Feb 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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

May 30, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	22
Dann	Uncertain	0.98
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.097
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.89	D;D
MetaRNN	Benign	0.0017	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.086
Sift	Benign	0.039	D;D
Sift4G	Benign	0.17	T;T
Vest4		0.21
MVP		0.16
ClinPred		0.017	T
GERP RS		3.3
Varity_R		0.093
gMVP		0.14

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

LitVar

Other links and lift over

dbSNP: rs61738656; hg19: chr11-116728913; COSMIC: COSV52615247; COSMIC: COSV52615247;