NM_015191.3:c.40C>T

Variant names:

• chr11-111602603-C-T
• rs1941598239
• NM_015191.3:c.40C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_015191.3(SIK2):​c.40C>T​(p.Pro14Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000217 in 1,380,760 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P14A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: SIK2 NM_015191.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.61
• Publications: 0 publications found

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]

ENSG00000309590 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015191.3. 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
	SIK2	NM_015191.3	MANE Select	c.40C>T	p.Pro14Ser	missense	Exon 1 of 15	NP_056006.1	Q9H0K1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIK2	ENST00000304987.4	TSL:1 MANE Select	c.40C>T	p.Pro14Ser	missense	Exon 1 of 15	ENSP00000305976.3	Q9H0K1
	SIK2	ENST00000876570.1		c.40C>T	p.Pro14Ser	missense	Exon 1 of 16	ENSP00000546629.1
	SIK2	ENST00000940048.1		c.40C>T	p.Pro14Ser	missense	Exon 1 of 15	ENSP00000610107.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000217 AC: 3 AN: 1380760 Hom.: 0 Cov.: 32 AF XY: 0.00000294 AC XY: 2 AN XY: 681404

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 28756

American (AMR) AF: 0.0000285 AC: 1 AN: 35088

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24380

East Asian (EAS) AF: 0.00 AC: 0 AN: 32092

South Asian (SAS) AF: 0.00 AC: 0 AN: 77748

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5452

European-Non Finnish (NFE) AF: 9.33e-7 AC: 1 AN: 1071648

Other (OTH) AF: 0.0000175 AC: 1 AN: 57228

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0160444), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	0.84	L
PhyloP100		4.6
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.031	D
Polyphen		0.95	P
Vest4		0.29
MutPred		0.32		Gain of MoRF binding (P = 0.0429)
MVP		0.22
MPC		2.3
ClinPred		0.99	D
GERP RS		4.3
PromoterAI		-0.027	Neutral
Varity_R		0.71
gMVP		0.45
Mutation Taster		=48/52	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1941598239; hg19: chr11-111473327;