Variant 1-206493333-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014002.4(IKBKE):c.2000C>G(p.Pro667Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

IKBKE
NM_014002.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.142

Variant links:

Genes affected

IKBKE (HGNC:14552): (inhibitor of nuclear factor kappa B kinase subunit epsilon) IKBKE is a noncanonical I-kappa-B (see MIM 164008) kinase (IKK) that is essential for regulating antiviral signaling pathways. IKBKE has also been identified as a breast cancer (MIM 114480) oncogene and is amplified and overexpressed in over 30% of breast carcinomas and breast cancer cell lines (Hutti et al., 2009 [PubMed 19481526]).[supplied by OMIM, Oct 2009]

IKBKE links:

IKBKE-AS1 (HGNC:32061): (IKBKE antisense RNA 1)

IKBKE-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08666548).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IKBKE	NM_014002.4 linkuse as main transcript	c.2000C>G	p.Pro667Arg	missense_variant	20/22	ENST00000581977.7	NP_054721.1
IKBKE-AS1	NR_172918.1 linkuse as main transcript	n.136-257G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IKBKE	ENST00000581977.7 linkuse as main transcript	c.2000C>G	p.Pro667Arg	missense_variant	20/22	1	NM_014002.4	ENSP00000464030	P1	Q14164-1
IKBKE	ENST00000584998.5 linkuse as main transcript	c.1745C>G	p.Pro582Arg	missense_variant	19/21	1		ENSP00000462396		Q14164-2
IKBKE	ENST00000578328.6 linkuse as main transcript	c.1932+214C>G		intron_variant		1		ENSP00000473833
IKBKE-AS1	ENST00000367119.1 linkuse as main transcript	n.136-257G>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461794

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727202

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2021

The c.2000C>G (p.P667R) alteration is located in exon 20 (coding exon 18) of the IKBKE gene. This alteration results from a C to G substitution at nucleotide position 2000, causing the proline (P) at amino acid position 667 to be replaced by an arginine (R). 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

0.086

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.13

.;T

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.096

LIST_S2

Benign

0.51

T;T

M_CAP

Benign

0.0032

MetaRNN

Benign

0.087

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

.;M

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.28

Sift4G

Benign

0.26

T;T

Polyphen

0.0080

.;B

Vest4

0.26

MutPred

0.18

.;Loss of glycosylation at P667 (P = 0.0076);

MVP

0.35

ClinPred

0.073

GERP RS

3.1

Varity_R

0.042

gMVP

0.18

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