chr1-206493333-C-G

Position:

• chr1-206493333-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.142

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

ACMG classification

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	c.2000C>G	p.Pro667Arg	missense_variant	20/22	ENST00000581977.7	NP_054721.1
IKBKE-AS1	NR_172918.1	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	c.2000C>G	p.Pro667Arg	missense_variant	20/22	1	NM_014002.4	ENSP00000464030	P1
IKBKE	ENST00000584998.5	c.1745C>G	p.Pro582Arg	missense_variant	19/21	1		ENSP00000462396
IKBKE	ENST00000578328.6	c.1932+214C>G		intron_variant		1		ENSP00000473833
IKBKE-AS1	ENST00000367119.1	n.136-257G>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461794 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727202

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.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	12
DANN	Benign	0.93
DEOGEN2	Benign	0.13	.;T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.096	N
LIST_S2	Benign	0.51	T;T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.087	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	.;M
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.28	T
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	T
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

Other links and lift over

dbSNP: rs1666050536; hg19: chr1-206666666;