rs768404256

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_173354.5(SIK1):c.2242C>T(p.Arg748Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/22 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. R748H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 0)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SIK1
NM_173354.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.36

Publications

0 publications found

Variant links:

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

SIK1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.061491936).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIK1	NM_173354.5 link	c.2242C>T	p.Arg748Cys	missense_variant	Exon 14 of 14	ENST00000270162.8	NP_775490.2	P57059
SIK1	XM_011529474.3 link	c.2095C>T	p.Arg699Cys	missense_variant	Exon 13 of 13		XP_011527776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIK1	ENST00000270162.8 link	c.2242C>T	p.Arg748Cys	missense_variant	Exon 14 of 14	1	NM_173354.5	ENSP00000270162.6		P57059

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000216

AC:

AN:

231844

AF XY:

0.0000314

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000582

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000290

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

40668

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

20682

African (AFR)

AF:

0.00

AC:

AN:

2570

American (AMR)

AF:

0.00

AC:

AN:

876

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2070

East Asian (EAS)

AF:

0.00

AC:

AN:

3802

South Asian (SAS)

AF:

0.00

AC:

AN:

1374

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1194

Middle Eastern (MID)

AF:

0.00

AC:

AN:

304

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

25350

Other (OTH)

AF:

0.00

AC:

AN:

3128

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000497

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jun 10, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2242C>T (p.R748C) alteration is located in exon 14 (coding exon 13) of the SIK1 gene. This alteration results from a C to T substitution at nucleotide position 2242, causing the arginine (R) at amino acid position 748 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Developmental and epileptic encephalopathy, 30

Uncertain:1

Mar 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 748 of the SIK1 protein (p.Arg748Cys). This variant is present in population databases (rs768404256, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with SIK1-related conditions. ClinVar contains an entry for this variant (Variation ID: 476103). 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 with a negative predictive value of 95%. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.076

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.51

M_CAP

Benign

0.0093

MetaRNN

Benign

0.061

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.69

PhyloP100

1.4

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.030

REVEL

Benign

0.16

Sift

Benign

0.26

Sift4G

Benign

0.061

Polyphen

0.0010

Vest4

0.14

MutPred

0.28

Gain of catalytic residue at L749 (P = 0.0174);

MVP

0.10

MPC

0.19

ClinPred

0.073

GERP RS

-2.2

Varity_R

0.041

gMVP

0.38

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over