rs6589574

Variant names:

• chr11-116859922-A-G
• rs6589574
• NM_001366686.3:c.2426-318T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001366686.3(SIK3):​c.2426-318T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.89 in 152,200 control chromosomes in the GnomAD database, including 60,597 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.89 (60597 hom., cov: 31)
• Consequence: SIK3 NM_001366686.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.834
• Publications: 12 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):

• spondyloepimetaphyseal dysplasia, Krakow type

  Inheritance: AR, Unknown Classification: MODERATE, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autism

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hearing loss disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.925 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIK3	NM_001366686.3	MANE Select	c.2426-318T>C		intron	N/A	NP_001353615.1	H0Y4E8
	SIK3	NM_025164.6		c.2282-318T>C		intron	N/A	NP_079440.3
	SIK3	NM_001281749.3		c.2282-318T>C		intron	N/A	NP_001268678.1	Q9Y2K2-8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIK3	ENST00000445177.6	TSL:5 MANE Select	c.2426-318T>C		intron	N/A	ENSP00000391295.2	H0Y4E8
	SIK3	ENST00000446921.6	TSL:1	c.2282-318T>C		intron	N/A	ENSP00000390442.2	Q9Y2K2-8
	SIK3	ENST00000415541.5	TSL:1	n.*1806-318T>C		intron	N/A	ENSP00000392761.1	H7C038

Frequencies

GnomAD3 genomes AF: 0.890 AC: 135339 AN: 152082 Hom.: 60556 Cov.: 31

Gnomad AFR AF: 0.933

Gnomad AMI AF: 0.987

Gnomad AMR AF: 0.829

Gnomad ASJ AF: 0.875

Gnomad EAS AF: 0.653

Gnomad SAS AF: 0.735

Gnomad FIN AF: 0.854

Gnomad MID AF: 0.870

Gnomad NFE AF: 0.912

Gnomad OTH AF: 0.890

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.890 AC: 135436 AN: 152200 Hom.: 60597 Cov.: 31 AF XY: 0.882 AC XY: 65635 AN XY: 74412

African (AFR) AF: 0.933 AC: 38760 AN: 41546

American (AMR) AF: 0.828 AC: 12670 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.875 AC: 3036 AN: 3468

East Asian (EAS) AF: 0.653 AC: 3375 AN: 5166

South Asian (SAS) AF: 0.736 AC: 3547 AN: 4820

European-Finnish (FIN) AF: 0.854 AC: 9042 AN: 10590

Middle Eastern (MID) AF: 0.871 AC: 256 AN: 294

European-Non Finnish (NFE) AF: 0.912 AC: 61983 AN: 68000

Other (OTH) AF: 0.885 AC: 1869 AN: 2112

Alfa AF: 0.907 Hom.: 84332

Bravo AF: 0.895

Asia WGS AF: 0.702 AC: 2444 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.026
DANN	Benign	0.35
PhyloP100		-0.83
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs6589574;

hg19: chr11-116730638;