NM_173354.5:c.2087C>T

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.2087C>T(p.Pro696Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. P696S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000020 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SIK1
NM_173354.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.359

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0032420158).

BP6

Variant 21-43417007-G-A is Benign according to our data. Variant chr21-43417007-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 376881.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.2087C>T	p.Pro696Leu	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.2087C>T	p.Pro696Leu	missense	Exon 14 of 14	ENSP00000270162.6	P57059
SIK1	ENST00000880890.1		c.1940C>T	p.Pro647Leu	missense	Exon 13 of 13	ENSP00000550949.1
SIK1	ENST00000880889.1		c.1805C>T	p.Pro602Leu	missense	Exon 13 of 13	ENSP00000550948.1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

3938

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:

0.00734

AC:

455

AN:

61998

AF XY:

0.00763

show subpopulations

Gnomad AFR exome

AF:

0.0257

Gnomad AMR exome

AF:

0.00682

Gnomad ASJ exome

AF:

0.00499

Gnomad EAS exome

AF:

0.000137

Gnomad FIN exome

AF:

0.00257

Gnomad NFE exome

AF:

0.00379

Gnomad OTH exome

AF:

0.00797

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000198

AC:

AN:

50602

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

25990

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

2970

American (AMR)

AF:

0.00

AC:

AN:

1086

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2442

East Asian (EAS)

AF:

0.00

AC:

AN:

5248

South Asian (SAS)

AF:

0.00142

AC:

AN:

706

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1710

Middle Eastern (MID)

AF:

0.00

AC:

AN:

338

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

32238

Other (OTH)

AF:

0.00

AC:

AN:

3864

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.825

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

3954

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

1714

African (AFR)

AF:

0.00

AC:

AN:

1888

American (AMR)

AF:

0.00

AC:

AN:

202

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

156

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:

1442

Other (OTH)

AF:

0.00

AC:

AN:

Alfa

AF:

0.00117

Hom.:

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.0155

AC:

ESP6500EA

AF:

0.00258

AC:

ExAC

AF:

0.00306

AC:

321

Asia WGS

AF:

0.00231

AC:

AN:

3476

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Developmental and epileptic encephalopathy, 30 (2)

not provided (2)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.55

CADD

Benign

2.4

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.092

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.50

MetaRNN

Benign

0.0032

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

PhyloP100

0.36

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.92

REVEL

Benign

0.070

Sift

Benign

0.035

Sift4G

Benign

0.45

Polyphen

0.0

Vest4

0.038

MVP

0.11

MPC

0.45

ClinPred

0.0041

GERP RS

-1.5

Varity_R

0.029

gMVP

0.25

Mutation Taster

=98/2

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over