dbSNP rs771103431: SIK1:p.Gly357Arg (chr21-43419909-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_ModerateBP6_Moderate

The NM_173354.5(SIK1):c.1069G>A(p.Gly357Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 0)

Exomes 𝑓: 0.000021 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SIK1
NM_173354.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.75

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 was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06887627).

BP6

Variant 21-43419909-C-T is Benign according to our data. Variant chr21-43419909-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 542698.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIK1	NM_173354.5 link	c.1069G>A	p.Gly357Arg	missense_variant	Exon 9 of 14	ENST00000270162.8	NP_775490.2	P57059
SIK1	XM_011529474.3 link	c.972+325G>A		intron_variant	Intron 8 of 12		XP_011527776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIK1	ENST00000270162.8 link	c.1069G>A	p.Gly357Arg	missense_variant	Exon 9 of 14	1	NM_173354.5	ENSP00000270162.6		P57059
SIK1	ENST00000644871.1 link	n.14G>A		non_coding_transcript_exon_variant	Exon 1 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000899

AC:

AN:

222400

AF XY:

0.0000744

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000377

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:

0.000362

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000207

AC:

AN:

48254

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

25516

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

1136

American (AMR)

AF:

0.00

AC:

AN:

524

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1614

East Asian (EAS)

AF:

0.00

AC:

AN:

3486

South Asian (SAS)

AF:

0.000254

AC:

AN:

3930

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1232

Middle Eastern (MID)

AF:

0.00

AC:

AN:

222

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

33416

Other (OTH)

AF:

0.00

AC:

AN:

2694

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.000836

Hom.:

ExAC

AF:

0.000116

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 30

Benign:1

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.74

M_CAP

Benign

0.044

MetaRNN

Benign

0.069

MetaSVM

Benign

-0.86

MutationAssessor

Uncertain

2.1

PhyloP100

1.8

PrimateAI

Benign

0.42

PROVEAN

Benign

0.21

REVEL

Benign

0.16

Sift

Benign

0.40

Sift4G

Benign

0.52

Polyphen

0.95

Vest4

0.16

MutPred

0.27

Gain of MoRF binding (P = 0.0234);

MVP

0.17

MPC

0.36

ClinPred

0.097

GERP RS

5.2

Varity_R

0.071

gMVP

0.23

Mutation Taster

=87/13

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

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rs771103431

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over