Genetic Variant SIKE1:p.Ile206Val (chr1-114774279-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_025073.3(SIKE1):c.616A>G(p.Ile206Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,608,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

SIKE1
NM_025073.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.33

Variant links:

Genes affected

SIKE1 (HGNC:26119): (suppressor of IKBKE 1) SIKE interacts with IKK-epsilon (IKBKE; MIM 605048) and TBK1 (MIM 604834) and acts as a suppressor of TLR3 (MIM 603029) and virus-triggered interferon activation pathways (Huang et al., 2005 [PubMed 16281057]).[supplied by OMIM, Mar 2008]

SIKE1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06761065).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIKE1	NM_025073.3 link	c.616A>G	p.Ile206Val	missense_variant	Exon 5 of 5	ENST00000060969.6	NP_079349.2	Q9BRV8-1
SIKE1	NM_001102396.2 link	c.628A>G	p.Ile210Val	missense_variant	Exon 5 of 5		NP_001095866.1	Q9BRV8-2
SIKE1	NR_049741.2 link	n.756A>G		non_coding_transcript_exon_variant	Exon 5 of 5
SIKE1	NR_049742.2 link	n.588A>G		non_coding_transcript_exon_variant	Exon 4 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SIKE1	ENST00000060969.6 link	c.616A>G	p.Ile206Val	missense_variant	Exon 5 of 5	1	NM_025073.3	ENSP00000060969.6	Q9BRV8-1
SIKE1	ENST00000369528.9 link	c.628A>G	p.Ile210Val	missense_variant	Exon 5 of 5	1		ENSP00000358541.5	Q9BRV8-2
SIKE1	ENST00000369524.5 link	n.318A>G		non_coding_transcript_exon_variant	Exon 3 of 3	3
SIKE1	ENST00000510745.5 link	n.*66A>G		downstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000800

AC:

AN:

250074

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135326

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000165

AC:

AN:

1456716

Hom.:

Cov.:

AF XY:

0.0000166

AC XY:

AN XY:

724816

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000812

Gnomad4 OTH exome

AF:

0.0000333

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.628A>G (p.I210V) alteration is located in exon 5 (coding exon 5) of the SIKE1 gene. This alteration results from a A to G substitution at nucleotide position 628, causing the isoleucine (I) at amino acid position 210 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.75

DEOGEN2

Benign

0.025

.;T

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.21

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.52

T;T

M_CAP

Benign

0.0019

MetaRNN

Benign

0.068

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.1

.;L

PrimateAI

Benign

0.35

PROVEAN

Benign

0.030

N;N

REVEL

Benign

0.029

Sift

Benign

0.29

T;T

Sift4G

Benign

0.62

T;T

Polyphen

0.0060

B;B

Vest4

0.045

MutPred

0.11

.;Gain of methylation at K207 (P = 0.0457);

MVP

0.36

MPC

0.30

ClinPred

0.068

GERP RS

3.7

Varity_R

0.020

gMVP

0.10

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over