1-206474380-T-C

Position:

• chr1-206474380-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014002.4(IKBKE):​c.137T>C​(p.Leu46Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: IKBKE NM_014002.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.48

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32649744).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IKBKE	NM_014002.4	c.137T>C	p.Leu46Pro	missense_variant	4/22	ENST00000581977.7	NP_054721.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IKBKE	ENST00000581977.7	c.137T>C	p.Leu46Pro	missense_variant	4/22	1	NM_014002.4	ENSP00000464030	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461704 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727174

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Jan 23, 2024

The c.137T>C (p.L46P) alteration is located in exon 4 (coding exon 2) of the IKBKE gene. This alteration results from a T to C substitution at nucleotide position 137, causing the leucine (L) at amino acid position 46 to be replaced by a proline (P). 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	Uncertain	0.39
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	.;T;T;T
Eigen	Benign	0.17
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.33	T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.9	.;L;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.47	T
Sift4G	Uncertain	0.049	D;T;D;T
Polyphen		0.98	.;D;.;.
Vest4		0.47
MutPred		0.52		Gain of disorder (P = 0.0131);Gain of disorder (P = 0.0131);Gain of disorder (P = 0.0131);Gain of disorder (P = 0.0131);
MVP		0.78
ClinPred		0.76	D
GERP RS		2.7
Varity_R		0.11
gMVP		0.61

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: rs1553384595; hg19: chr1-206647723;