11-111602603-C-G

Position:

• chr11-111602603-C-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_015191.3(SIK2):​c.40C>G​(p.Pro14Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000174 in 1,380,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: SIK2 NM_015191.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.61

Genes affected

SIK2 (HGNC:21680): (salt inducible kinase 2) Enables ATP binding activity; magnesium ion binding activity; and protein serine/threonine kinase activity. Involved in intracellular signal transduction and protein autophosphorylation. Predicted to be located in nucleus. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.37703425).
• BS2: High AC in GnomAdExome4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIK2	NM_015191.3	c.40C>G	p.Pro14Ala	missense_variant	1/15	ENST00000304987.4	NP_056006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SIK2	ENST00000304987.4	c.40C>G	p.Pro14Ala	missense_variant	1/15	1	NM_015191.3	ENSP00000305976.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000174 AC: 24 AN: 1380760 Hom.: 0 Cov.: 32 AF XY: 0.0000132 AC XY: 9 AN XY: 681404

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000215

Gnomad4 OTH exome AF: 0.0000175

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000625 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 31, 2023

The c.40C>G (p.P14A) alteration is located in exon 1 (coding exon 1) of the SIK2 gene. This alteration results from a C to G substitution at nucleotide position 40, causing the proline (P) at amino acid position 14 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	0.0095	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.87	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	0.82	L
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-4.9	D
REVEL	Uncertain	0.44
Sift	Benign	0.072	T
Sift4G	Benign	0.12	T
Polyphen		0.64	P
Vest4		0.26
MutPred		0.39		Gain of MoRF binding (P = 0.0334);
MVP		0.19
MPC		2.2
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.56
gMVP		0.37

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: rs1941598239; hg19: chr11-111473327;