rs430554

Positions:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_173354.5(SIK1):c.1844C>T(p.Ala615Val) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein 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: 𝑓 0.057 ( 498 hom., cov: 0)

Exomes 𝑓: 0.065 ( 9830 hom. )

Failed GnomAD Quality Control

Consequence

SIK1
NM_173354.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 5.79

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.6161289E-6).

BP6

Variant 21-43417675-G-A is Benign according to our data. Variant chr21-43417675-G-A is described in ClinVar as [Benign]. Clinvar id is 586585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIK1	NM_173354.5 linkuse as main transcript	c.1844C>T	p.Ala615Val	missense_variant	13/14	ENST00000270162.8
SIK1	XM_011529474.3 linkuse as main transcript	c.1697C>T	p.Ala566Val	missense_variant	12/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIK1	ENST00000270162.8 linkuse as main transcript	c.1844C>T	p.Ala615Val	missense_variant	13/14	1	NM_173354.5	P1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

2139

AN:

37422

Hom.:

495

Cov.:

FAILED QC

Gnomad AFR

AF:

0.0558

Gnomad AMI

AF:

0.00806

Gnomad AMR

AF:

0.0392

Gnomad ASJ

AF:

0.0626

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0351

Gnomad FIN

AF:

0.0702

Gnomad MID

AF:

0.159

Gnomad NFE

AF:

0.0663

Gnomad OTH

AF:

0.0527

GnomAD3 exomes

AF:

0.888

AC:

192033

AN:

216326

Hom.:

85333

AF XY:

0.887

AC XY:

104913

AN XY:

118324

show subpopulations

Gnomad AFR exome

AF:

0.736

Gnomad AMR exome

AF:

0.941

Gnomad ASJ exome

AF:

0.841

Gnomad EAS exome

AF:

0.900

Gnomad SAS exome

AF:

0.852

Gnomad FIN exome

AF:

0.961

Gnomad NFE exome

AF:

0.889

Gnomad OTH exome

AF:

0.875

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0649

AC:

21219

AN:

327096

Hom.:

9830

Cov.:

AF XY:

0.0680

AC XY:

10998

AN XY:

161722

show subpopulations

Gnomad4 AFR exome

AF:

0.0721

Gnomad4 AMR exome

AF:

0.0921

Gnomad4 ASJ exome

AF:

0.136

Gnomad4 EAS exome

AF:

0.000921

Gnomad4 SAS exome

AF:

0.0543

Gnomad4 FIN exome

AF:

0.267

Gnomad4 NFE exome

AF:

0.0588

Gnomad4 OTH exome

AF:

0.0999

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0573

AC:

2147

AN:

37466

Hom.:

498

Cov.:

AF XY:

0.0563

AC XY:

984

AN XY:

17480

show subpopulations

Gnomad4 AFR

AF:

0.0560

Gnomad4 AMR

AF:

0.0392

Gnomad4 ASJ

AF:

0.0626

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0352

Gnomad4 FIN

AF:

0.0702

Gnomad4 NFE

AF:

0.0663

Gnomad4 OTH

AF:

0.0562

Alfa

AF:

0.846

Hom.:

50165

TwinsUK

AF:

0.875

AC:

3243

ALSPAC

AF:

0.873

AC:

3365

ESP6500AA

AF:

0.757

AC:

3275

ESP6500EA

AF:

0.890

AC:

7596

ExAC

AF:

0.866

AC:

102141

Asia WGS

AF:

0.849

AC:

2955

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 30

Benign:3

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 30, 2018	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jul 31, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 100% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 93. Only high quality variants are reported. -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 31, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.089

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.48

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.51

MetaRNN

Benign

0.0000016

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

MutationTaster

Benign

1.0

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.90

REVEL

Benign

0.20

Sift

Uncertain

0.0050

Sift4G

Benign

0.28

Polyphen

0.28

Vest4

0.039

MPC

0.16

ClinPred

0.032

GERP RS

2.3

Varity_R

0.088

gMVP

0.12

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over