21-43417585-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_173354.5(SIK1):c.1934G>A(p.Arg645Gln) variant causes a missense change. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R645W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 1)

Exomes 𝑓: 0.000073 ( 4 hom. )

Failed GnomAD Quality Control

Consequence

SIK1
NM_173354.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 3.69

Publications

2 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: Labcorp Genetics (formerly Invitae), G2P
early myoclonic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
genetic developmental and epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: ClinGen, 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: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.097569525).

BP6

Variant 21-43417585-C-T is Benign according to our data. Variant chr21-43417585-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 542710.

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.1934G>A	p.Arg645Gln	missense	Exon 13 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.1934G>A	p.Arg645Gln	missense	Exon 13 of 14	ENSP00000270162.6	P57059
SIK1	ENST00000880890.1		c.1787G>A	p.Arg596Gln	missense	Exon 12 of 13	ENSP00000550949.1
SIK1	ENST00000880889.1		c.1652G>A	p.Arg551Gln	missense	Exon 12 of 13	ENSP00000550948.1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

34682

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

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:

0.0000479

AC:

AN:

125242

AF XY:

0.0000570

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000133

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000213

Gnomad FIN exome

AF:

0.0000631

Gnomad NFE exome

AF:

0.0000162

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000730

AC:

AN:

164442

Hom.:

Cov.:

AF XY:

0.0000602

AC XY:

AN XY:

83086

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

8312

American (AMR)

AF:

0.00

AC:

AN:

1666

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

4650

East Asian (EAS)

AF:

0.000648

AC:

AN:

6176

South Asian (SAS)

AF:

0.00

AC:

AN:

9772

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3770

Middle Eastern (MID)

AF:

0.00

AC:

AN:

700

European-Non Finnish (NFE)

AF:

0.0000666

AC:

AN:

120164

Other (OTH)

AF:

0.00

AC:

AN:

9232

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

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: AC0

AF:

0.00

AC:

AN:

34726

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

15980

African (AFR)

AF:

0.00

AC:

AN:

15546

American (AMR)

AF:

0.00

AC:

AN:

2070

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1004

East Asian (EAS)

AF:

0.00

AC:

AN:

738

South Asian (SAS)

AF:

0.00

AC:

AN:

1004

European-Finnish (FIN)

AF:

0.00

AC:

AN:

558

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

13060

Other (OTH)

AF:

0.00

AC:

AN:

460

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000428

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Developmental and epileptic encephalopathy, 30 (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.34

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.61

M_CAP

Benign

0.035

MetaRNN

Benign

0.098

MetaSVM

Benign

-0.79

MutationAssessor

Benign

2.0

PhyloP100

3.7

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.89

REVEL

Benign

0.16

Sift

Uncertain

0.0040

Sift4G

Benign

0.35

Polyphen

0.052

Vest4

0.28

MutPred

0.13

Loss of glycosylation at S644 (P = 0.0934)

MVP

0.70

MPC

0.44

ClinPred

0.14

GERP RS

4.1

Varity_R

0.16

gMVP

0.34

Mutation Taster

=96/4

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over