rs3746951

Variant names:

• chr21-43426136-C-A
• rs3746951
• NM_173354.5:c.43G>T

Your query was ambiguous. Multiple possible variants found:

• chr21-43426136-C-A
• chr21-43426136-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_173354.5(SIK1):​c.43G>T​(p.Gly15Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G15S) has been classified as Benign.

• Frequency: Genomes: not found (cov: 0)
• Consequence: SIK1 NM_173354.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.03
• Publications: 26 publications found

Genes affected

SIK1 (HGNC:11142): (salt inducible kinase 1) This gene encodes a serine/threonine protein kinase that contains a ubiquitin-associated (UBA) domain. The encoded protein is a member of the adenosine monophosphate-activated kinase (AMPK) subfamily of kinases that play a role in conserved signal transduction pathways. A mutation in this gene is associated with early infantile epileptic encephalopathy 30. [provided by RefSeq, Nov 2016]

SIK1 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 30

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• early myoclonic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• generalized epilepsy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2363278).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIK1	NM_173354.5	c.43G>T	p.Gly15Cys	missense_variant	Exon 2 of 14	ENST00000270162.8	NP_775490.2
SIK1	XM_011529474.3	c.43G>T	p.Gly15Cys	missense_variant	Exon 2 of 13		XP_011527776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIK1	ENST00000270162.8	c.43G>T	p.Gly15Cys	missense_variant	Exon 2 of 14	1	NM_173354.5	ENSP00000270162.6
SIK1	ENST00000644750.1	c.43G>T	p.Gly15Cys	missense_variant	Exon 2 of 5			ENSP00000495479.1
SIK1	ENST00000644276.1	n.140G>T		non_coding_transcript_exon_variant	Exon 2 of 3

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 30 Uncertain:1

Jul 27, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SIK1 protein function. This variant has not been reported in the literature in individuals affected with SIK1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 15 of the SIK1 protein (p.Gly15Cys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;.
Eigen	Benign	-0.092
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.56	T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.0	L;.
PhyloP100		1.0
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.0	N;.
REVEL	Benign	0.14
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.010	D;.
Polyphen		0.99	D;.
Vest4		0.18
MutPred		0.38		Loss of disorder (P = 0.0354);Loss of disorder (P = 0.0354);
MVP		0.31
MPC		2.0
ClinPred		0.59	D
GERP RS		2.4
Varity_R		0.32
gMVP		0.37
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs3746951; hg19: chr21-44846016;