1-206493987-G-C

Position:

• chr1-206493987-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014002.4(IKBKE):​c.2113G>C​(p.Glu705Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: IKBKE NM_014002.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.72

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IKBKE	NM_014002.4	c.2113G>C	p.Glu705Gln	missense_variant	21/22	ENST00000581977.7	NP_054721.1
IKBKE-AS1	NR_172918.1	n.136-911C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IKBKE	ENST00000581977.7	c.2113G>C	p.Glu705Gln	missense_variant	21/22	1	NM_014002.4	ENSP00000464030	P1
IKBKE	ENST00000584998.5	c.1858G>C	p.Glu620Gln	missense_variant	20/21	1		ENSP00000462396
IKBKE	ENST00000578328.6	c.*26G>C		3_prime_UTR_variant	20/21	1		ENSP00000473833
IKBKE-AS1	ENST00000367119.1	n.136-911C>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

May 01, 2022

The c.2113G>C (p.E705Q) alteration is located in exon 21 (coding exon 19) of the IKBKE gene. This alteration results from a G to C substitution at nucleotide position 2113, causing the glutamic acid (E) at amino acid position 705 to be replaced by a glutamine (Q). 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	0.12
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	.;T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.080	D
MetaRNN	Uncertain	0.44	T;T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Uncertain	2.8	.;M
MutationTaster	Benign	0.95	D;D;D
PrimateAI	Benign	0.41	T
Sift4G	Uncertain	0.056	T;T
Polyphen		0.97	.;D
Vest4		0.34
MutPred		0.34		.;Gain of MoRF binding (P = 0.0779);
MVP		0.89
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.094
gMVP		0.21

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: rs1553391457; hg19: chr1-206667320;