Genetic Variant SIK1:p.Gly636Ser (chr21-43417613-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP5BP4

The NM_173354.5(SIK1):c.1906G>A(p.Gly636Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. G636G) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 1)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SIK1
NM_173354.5 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 0.899

Publications

2 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: Uncertain_significance. The variant received 0 ACMG points.

PP5

Variant 21-43417613-C-T is Pathogenic according to our data. Variant chr21-43417613-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 190109.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.088878006). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIK1	NM_173354.5 link	c.1906G>A	p.Gly636Ser	missense_variant	Exon 13 of 14	ENST00000270162.8	NP_775490.2	P57059
SIK1	XM_011529474.3 link	c.1759G>A	p.Gly587Ser	missense_variant	Exon 12 of 13		XP_011527776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIK1	ENST00000270162.8 link	c.1906G>A	p.Gly636Ser	missense_variant	Exon 13 of 14	1	NM_173354.5	ENSP00000270162.6		P57059

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

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

AF:

0.00

AC:

AN:

281374

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

138464

African (AFR)

AF:

0.00

AC:

AN:

12080

American (AMR)

AF:

0.00

AC:

AN:

2056

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5858

East Asian (EAS)

AF:

0.00

AC:

AN:

6510

South Asian (SAS)

AF:

0.00

AC:

AN:

15522

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4736

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1046

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

219894

Other (OTH)

AF:

0.00

AC:

AN:

13672

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 30

Pathogenic:1

Apr 02, 2015

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.075

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.63

M_CAP

Benign

0.011

MetaRNN

Benign

0.089

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.1

PhyloP100

0.90

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.30

REVEL

Benign

0.084

Sift

Benign

0.25

Sift4G

Benign

1.0

Polyphen

0.010

Vest4

0.12

MutPred

0.17

Gain of glycosylation at G636 (P = 0.0042);

MVP

0.44

MPC

0.16

ClinPred

0.073

GERP RS

-0.48

Varity_R

0.038

gMVP

0.17

Mutation Taster

=96/4

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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