chr11-116857914-G-C

Variant names:

• chr11-116857914-G-C
• rs12225230
• NM_001366686.3:c.3551C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. 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:3
• Conservation: PhyloP100: 5.16
• Publications: 49 publications found

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)

ACMG classification

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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001366686.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIK3	NM_001366686.3	MANE Select	c.3551C>G	p.Pro1184Arg	missense	Exon 21 of 25	NP_001353615.1
	SIK3	NM_025164.6		c.3407C>G	p.Pro1136Arg	missense	Exon 20 of 24	NP_079440.3
	SIK3	NM_001281749.3		c.3227C>G	p.Pro1076Arg	missense	Exon 20 of 24	NP_001268678.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIK3	ENST00000445177.6	TSL:5 MANE Select	c.3551C>G	p.Pro1184Arg	missense	Exon 21 of 25	ENSP00000391295.2
	SIK3	ENST00000446921.6	TSL:1	c.3227C>G	p.Pro1076Arg	missense	Exon 20 of 24	ENSP00000390442.2
	SIK3	ENST00000415541.5	TSL:1	n.*2751C>G		non_coding_transcript_exon	Exon 21 of 25	ENSP00000392761.1

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

GnomAD2 exomes AF: 0.188 AC: 47169 AN: 251452 AF XY: 0.190

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.: 33 AF XY: 0.182 AC XY: 132296 AN XY: 727230

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

GnomAD4 genome AF: 0.171 AC: 25936 AN: 152102 Hom.: 2320 Cov.: 32 AF XY: 0.172 AC XY: 12824 AN XY: 74366

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: 50 AN: 294

European-Non Finnish (NFE) AF: 0.181 AC: 12330 AN: 68004

Other (OTH) AF: 0.165 AC: 349 AN: 2112

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	SIK3-related disorder (1)
-	-	1	Spondyloepimetaphyseal dysplasia, Krakow type (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
PhyloP100		5.2
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.14
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.038	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
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

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