rs35596465

Variant names:

Variant summary

Our verdict is Benign. The variant received -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 Likely 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:3

Conservation

PhyloP100: 8.45

Publications

3 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: Benign. The variant received -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/Likely_benign. ClinVar VariationId is 476101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIK1	NM_173354.5 link	c.2174C>T	p.Ala725Val	missense_variant	Exon 14 of 14	ENST00000270162.8	NP_775490.2	P57059
SIK1	XM_011529474.3 link	c.2027C>T	p.Ala676Val	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.2174C>T	p.Ala725Val	missense_variant	Exon 14 of 14	1	NM_173354.5	ENSP00000270162.6		P57059

Frequencies

GnomAD3 genomes

AF:

0.0513

AC:

AN:

1852

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00306

AC:

429

AN:

140164

AF XY:

0.00240

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 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

African (AFR)

AF:

0.126

AC:

364

AN:

2886

American (AMR)

AF:

0.0530

AC:

AN:

1056

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2410

East Asian (EAS)

AF:

0.00

AC:

AN:

5076

South Asian (SAS)

AF:

0.00

AC:

AN:

680

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1634

Middle Eastern (MID)

AF:

0.0117

AC:

AN:

342

European-Non Finnish (NFE)

AF:

0.00109

AC:

AN:

31282

Other (OTH)

AF:

0.0300

AC:

115

AN:

3828

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.559

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

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

African (AFR)

AF:

0.0915

AC:

AN:

798

American (AMR)

AF:

0.183

AC:

AN:

120

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

676

Other (OTH)

AF:

0.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00353

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:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Jul 29, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Developmental and epileptic encephalopathy, 30

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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

PhyloP100

8.4

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

Mutation Taster

=75/25

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

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over