1-206493084-A-G

Position:

• chr1-206493084-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014002.4(IKBKE):​c.1897A>G​(p.Thr633Ala) 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. 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)
• Consequence: IKBKE NM_014002.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.443

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 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=0.065163136).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IKBKE	NM_014002.4	c.1897A>G	p.Thr633Ala	missense_variant	19/22	ENST00000581977.7	NP_054721.1
IKBKE-AS1	NR_172918.1	n.136-8T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IKBKE	ENST00000581977.7	c.1897A>G	p.Thr633Ala	missense_variant	19/22	1	NM_014002.4	ENSP00000464030	P1
IKBKE	ENST00000578328.6	c.1897A>G	p.Thr633Ala	missense_variant	19/21	1		ENSP00000473833
IKBKE	ENST00000584998.5	c.1642A>G	p.Thr548Ala	missense_variant	18/21	1		ENSP00000462396
IKBKE-AS1	ENST00000367119.1	n.136-8T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Dec 02, 2022

The c.1897A>G (p.T633A) alteration is located in exon 19 (coding exon 17) of the IKBKE gene. This alteration results from a A to G substitution at nucleotide position 1897, causing the threonine (T) at amino acid position 633 to be replaced by an alanine (A). 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	0.067
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	8.5
DANN	Benign	0.63
DEOGEN2	Benign	0.077	.;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.61	T;T;T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.065	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.2	.;.;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.36	T
Sift4G	Benign	0.77	T;T;T
Polyphen		0.0	.;.;B
Vest4		0.29
MutPred		0.28		Loss of catalytic residue at T633 (P = 0.0022);.;Loss of catalytic residue at T633 (P = 0.0022);
MVP		0.30
ClinPred		0.028	T
GERP RS		0.076
Varity_R		0.036
gMVP		0.091

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: chr1-206666417;