rs201955244

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.2204G>A(p.Gly735Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0045 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0013 ( 26 hom. )

Failed GnomAD Quality Control

Consequence

SIK1
NM_173354.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 3.08

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)
genetic developmental and epileptic encephalopathy
Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: PanelApp Australia, Orphanet, ClinGen
early myoclonic 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

new If you want to explore the variant's impact on the transcript NM_173354.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003515929).

BP6

Variant 21-43416890-C-T is Benign according to our data. Variant chr21-43416890-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 476102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173354.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIK1	NM_173354.5	MANE Select	c.2204G>A	p.Gly735Asp	missense	Exon 14 of 14	NP_775490.2	P57059

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SIK1	ENST00000270162.8	TSL:1 MANE Select	c.2204G>A	p.Gly735Asp	missense	Exon 14 of 14	ENSP00000270162.6	P57059
SIK1	ENST00000880890.1		c.2057G>A	p.Gly686Asp	missense	Exon 13 of 13	ENSP00000550949.1
SIK1	ENST00000880889.1		c.1922G>A	p.Gly641Asp	missense	Exon 13 of 13	ENSP00000550948.1

Frequencies

GnomAD3 genomes

AF:

0.00453

AC:

AN:

1104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0105

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000323

AC:

AN:

173342

AF XY:

0.000283

show subpopulations

Gnomad AFR exome

AF:

0.00555

Gnomad AMR exome

AF:

0.0000372

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00131

AC:

AN:

47418

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

AN XY:

24352

show subpopulations

African (AFR)

AF:

0.0161

AC:

AN:

2852

American (AMR)

AF:

0.00

AC:

AN:

1076

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2366

East Asian (EAS)

AF:

0.00

AC:

AN:

4724

South Asian (SAS)

AF:

0.00

AC:

AN:

940

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1520

Middle Eastern (MID)

AF:

0.00

AC:

AN:

334

European-Non Finnish (NFE)

AF:

0.000133

AC:

AN:

29964

Other (OTH)

AF:

0.00329

AC:

AN:

3642

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.615

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:

0.00447

AC:

AN:

1118

Hom.:

Cov.:

AF XY:

0.0111

AC XY:

AN XY:

452

show subpopulations

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

African (AFR)

AF:

0.0103

AC:

AN:

486

American (AMR)

AF:

0.00

AC:

AN:

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:

370

Other (OTH)

AF:

0.00

AC:

AN:

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000924279), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.365

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000812

Hom.:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Developmental and epileptic encephalopathy, 30 (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.076

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.29

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.55

M_CAP

Benign

0.037

MetaRNN

Benign

0.0035

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.34

PhyloP100

3.1

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.18

REVEL

Benign

0.096

Sift

Benign

0.046

Sift4G

Benign

0.45

Varity_R

0.13

gMVP

0.51

Mutation Taster

=92/8

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over