1-206478997-C-A

Position:

• chr1-206478997-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014002.4(IKBKE):​c.1047C>A​(p.His349Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IKBKE NM_014002.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.00200

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]

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=0.2044906).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IKBKE	NM_014002.4	c.1047C>A	p.His349Gln	missense_variant	10/22	ENST00000581977.7	NP_054721.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IKBKE	ENST00000581977.7	c.1047C>A	p.His349Gln	missense_variant	10/22	1	NM_014002.4	ENSP00000464030	P1
IKBKE	ENST00000578328.6	c.1047C>A	p.His349Gln	missense_variant	10/21	1		ENSP00000473833
IKBKE	ENST00000584998.5	c.792C>A	p.His264Gln	missense_variant	9/21	1		ENSP00000462396

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Jun 29, 2023

The c.1047C>A (p.H349Q) alteration is located in exon 10 (coding exon 8) of the IKBKE gene. This alteration results from a C to A substitution at nucleotide position 1047, causing the histidine (H) at amino acid position 349 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	0.13
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.12	.;.;T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.58	T;T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	2.0	.;.;M
MutationTaster	Benign	0.77	N;N
PrimateAI	Benign	0.40	T
Sift4G	Benign	0.69	T;T;T
Polyphen		0.083	.;.;B
Vest4		0.13
MutPred		0.27		Gain of disorder (P = 0.1547);.;Gain of disorder (P = 0.1547);
MVP		0.71
ClinPred		0.20	T
GERP RS		2.0
Varity_R		0.075
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-206652340;