rs430554

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.1844C>T(p.Ala615Val) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in 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:8

Conservation

PhyloP100: 5.79

Publications

25 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=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 VariationId is 586585.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.1844C>T	p.Ala615Val	missense_variant	Exon 13 of 14	ENST00000270162.8	NP_775490.2
SIK1	XM_011529474.3 link	c.1697C>T	p.Ala566Val	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.1844C>T	p.Ala615Val	missense_variant	Exon 13 of 14	1	NM_173354.5	ENSP00000270162.6

Frequencies

GnomAD3 genomes

AF:

0.0572

AC:

2139

AN:

37422

Hom.:

495

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.888

AC:

192033

AN:

216326

AF XY:

0.887

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0721

AC:

1008

AN:

13974

American (AMR)

AF:

0.0921

AC:

376

AN:

4082

Ashkenazi Jewish (ASJ)

AF:

0.136

AC:

926

AN:

6784

East Asian (EAS)

AF:

0.000921

AC:

AN:

7598

South Asian (SAS)

AF:

0.0543

AC:

1102

AN:

20286

European-Finnish (FIN)

AF:

0.267

AC:

1268

AN:

4756

Middle Eastern (MID)

AF:

0.0989

AC:

130

AN:

1314

European-Non Finnish (NFE)

AF:

0.0588

AC:

14878

AN:

253046

Other (OTH)

AF:

0.0999

AC:

1524

AN:

15256

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.270

Heterozygous variant carriers

175

349

524

698

873

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

162

216

270

<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:

0.0573

AC:

2147

AN:

37466

Hom.:

498

Cov.:

AF XY:

0.0563

AC XY:

984

AN XY:

17480

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0560

AC:

897

AN:

16012

American (AMR)

AF:

0.0392

AC:

AN:

2372

Ashkenazi Jewish (ASJ)

AF:

0.0626

AC:

AN:

990

East Asian (EAS)

AF:

0.00

AC:

AN:

878

South Asian (SAS)

AF:

0.0352

AC:

AN:

1194

European-Finnish (FIN)

AF:

0.0702

AC:

AN:

798

Middle Eastern (MID)

AF:

0.159

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0663

AC:

953

AN:

14376

Other (OTH)

AF:

0.0562

AC:

AN:

516

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.273

Heterozygous variant carriers

118

236

354

472

590

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.855

Hom.:

75693

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:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 30, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 20, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Developmental and epileptic encephalopathy, 30

Benign:3

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Jul 31, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Dec 31, 2015

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. -

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

(source)

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

PhyloP100

5.8

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

Mutation Taster

=70/30

polymorphism

(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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over