Genetic Variant SIK1:p.Ala615Ser (chr21-43417676-C-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

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

The NM_173354.5(SIK1):c.1843G>T(p.Ala615Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 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. A615T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 0)

Exomes 𝑓: 0.0000059 ( 1 hom. )

Consequence

SIK1
NM_173354.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.468

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=0.025228262).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIK1	NM_173354.5 link	c.1843G>T	p.Ala615Ser	missense_variant	Exon 13 of 14	ENST00000270162.8	NP_775490.2	P57059
SIK1	XM_011529474.3 link	c.1696G>T	p.Ala566Ser	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.1843G>T	p.Ala615Ser	missense_variant	Exon 13 of 14	1	NM_173354.5	ENSP00000270162.6		P57059

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000591

AC:

AN:

338508

Hom.:

Cov.:

AF XY:

0.0000119

AC XY:

AN XY:

167566

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

15104

American (AMR)

AF:

0.00

AC:

AN:

4080

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

7116

East Asian (EAS)

AF:

0.00

AC:

AN:

7506

South Asian (SAS)

AF:

0.00

AC:

AN:

21320

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4802

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1074

European-Non Finnish (NFE)

AF:

0.00000765

AC:

AN:

261558

Other (OTH)

AF:

0.00

AC:

AN:

15948

Age Distribution

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.59

CADD

Benign

1.7

(source)

DANN

Benign

0.65

DEOGEN2

Benign

0.070

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.52

M_CAP

Benign

0.0086

MetaRNN

Benign

0.025

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.48

PhyloP100

0.47

PrimateAI

Benign

0.42

PROVEAN

Benign

0.70

REVEL

Benign

0.088

Sift

Benign

1.0

Sift4G

Benign

0.93

Polyphen

0.0020

Vest4

0.045

MutPred

0.11

Gain of phosphorylation at A615 (P = 0.0889);

MVP

0.24

MPC

0.12

ClinPred

0.044

GERP RS

-5.4

Varity_R

0.030

gMVP

0.064

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over