Variant 21-43416920-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_173354.5(SIK1):c.2174C>T(p.Ala725Val) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A725T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.051 ( 17 hom., cov: 0)

Exomes 𝑓: 0.012 ( 231 hom. )

Failed GnomAD Quality Control

Consequence

SIK1
NM_173354.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 8.45

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=0.0021226406).

BP6

Variant 21-43416920-G-A is Benign according to our data. Variant chr21-43416920-G-A is described in ClinVar as [Benign]. Clinvar id is 476101.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.2174C>T	p.Ala725Val	missense_variant	14/14	ENST00000270162.8
SIK1	XM_011529474.3 linkuse as main transcript	c.2027C>T	p.Ala676Val	missense_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIK1	ENST00000270162.8 linkuse as main transcript	c.2174C>T	p.Ala725Val	missense_variant	14/14	1	NM_173354.5	P1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

1852

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.0929

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.183

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00306

AC:

429

AN:

140164

Hom.:

AF XY:

0.00240

AC XY:

183

AN XY:

76330

show subpopulations

Gnomad AFR exome

AF:

0.0432

Gnomad AMR exome

AF:

0.00304

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000349

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000537

Gnomad OTH exome

AF:

0.00290

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0116

AC:

573

AN:

49194

Hom.:

231

Cov.:

AF XY:

0.0109

AC XY:

275

AN XY:

25230

show subpopulations

Gnomad4 AFR exome

AF:

0.126

Gnomad4 AMR exome

AF:

0.0530

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00109

Gnomad4 OTH exome

AF:

0.0300

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0510

AC:

AN:

1864

Hom.:

Cov.:

AF XY:

0.0566

AC XY:

AN XY:

760

show subpopulations

Gnomad4 AFR

AF:

0.0915

Gnomad4 AMR

AF:

0.183

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00335

Hom.:

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0411

AC:

171

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00249

AC:

274

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 29, 2016

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. -

Developmental and epileptic encephalopathy, 30

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.12

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

MetaRNN

Benign

0.0021

MetaSVM

Benign

-0.50

MutationAssessor

Benign

1.9

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.3

REVEL

Uncertain

0.32

Sift

Pathogenic

0.0

Sift4G

Benign

0.091

Polyphen

1.0

Vest4

0.46

MVP

0.46

MPC

0.60

ClinPred

0.025

GERP RS

5.1

Varity_R

0.39

gMVP

0.47

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

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