rs745541081

chr21-43421772-C-T

Variant summary

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

The NM_173354.5(SIK1):c.365G>A(p.Ser122Asn) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 0)
• Consequence: SIK1 NM_173354.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.58

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.29901677).
• BS2: High AC in GnomAdExome at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIK1	NM_173354.5	c.365G>A	p.Ser122Asn	missense_variant	5/14	ENST00000270162.8
SIK1	XM_011529474.3	c.365G>A	p.Ser122Asn	missense_variant	5/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIK1	ENST00000270162.8	c.365G>A	p.Ser122Asn	missense_variant	5/14	1	NM_173354.5	P1
SIK1	ENST00000644750.1	c.365G>A	p.Ser122Asn	missense_variant	5/5
SIK1	ENST00000478426.1	n.234G>A		non_coding_transcript_exon_variant	1/3	3
SIK1	ENST00000644689.1	n.167G>A		non_coding_transcript_exon_variant	2/5

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD3 exomes AF: 0.0000200 AC: 5 AN: 250458 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135614

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

Alfa AF: 0.0000530 Hom.: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 30 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 24, 2022	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. ClinVar contains an entry for this variant (Variation ID: 542709). This variant has not been reported in the literature in individuals affected with SIK1-related conditions. This variant is present in population databases (rs745541081, gnomAD 0.006%). This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 122 of the SIK1 protein (p.Ser122Asn). -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Benign	0.11	T;.
Eigen	Benign	-0.098
Eigen_PC	Benign	-0.039
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.85	T;D
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.4	N;.
REVEL	Benign	0.065
Sift	Benign	0.26	T;.
Sift4G	Benign	0.23	T;.
Polyphen		0.42	B;.
Vest4		0.32
MVP		0.22
MPC		1.6
ClinPred		0.48	T
GERP RS		4.4
Varity_R		0.28
gMVP		0.59

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

Publications

LitVar

Other links and lift over

dbSNP: rs745541081; hg19: chr21-44841652;