1-206496132-C-T

Position:

• chr1-206496132-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014002.4(IKBKE):​c.2138C>T​(p.Pro713Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.205 in 1,610,104 control chromosomes in the GnomAD database, including 36,569 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.17 (2877 hom., cov: 32)
  • Exomes 𝑓: 0.21 (33692 hom.)
• Consequence: IKBKE NM_014002.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.15

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047554076).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.236 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IKBKE	NM_014002.4	c.2138C>T	p.Pro713Leu	missense_variant	22/22	ENST00000581977.7
IKBKE-AS1	NR_172918.1	n.135+1462G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IKBKE	ENST00000581977.7	c.2138C>T	p.Pro713Leu	missense_variant	22/22	1	NM_014002.4	P1
IKBKE	ENST00000584998.5	c.1883C>T	p.Pro628Leu	missense_variant	21/21	1
IKBKE	ENST00000578328.6	c.*51C>T		3_prime_UTR_variant	21/21	1
IKBKE-AS1	ENST00000367119.1	n.135+1462G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26174 AN: 151970 Hom.: 2880 Cov.: 32

Gnomad AFR AF: 0.0430

Gnomad AMI AF: 0.237

Gnomad AMR AF: 0.243

Gnomad ASJ AF: 0.157

Gnomad EAS AF: 0.200

Gnomad SAS AF: 0.0921

Gnomad FIN AF: 0.268

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.223

Gnomad OTH AF: 0.206

GnomAD3 exomes AF: 0.199 AC: 50019 AN: 250932 Hom.: 5597 AF XY: 0.197 AC XY: 26726 AN XY: 135676

Gnomad AFR exome AF: 0.0358

Gnomad AMR exome AF: 0.269

Gnomad ASJ exome AF: 0.145

Gnomad EAS exome AF: 0.216

Gnomad SAS exome AF: 0.0845

Gnomad FIN exome AF: 0.259

Gnomad NFE exome AF: 0.223

Gnomad OTH exome AF: 0.210

GnomAD4 exome AF: 0.209 AC: 304607 AN: 1458016 Hom.: 33692 Cov.: 30 AF XY: 0.206 AC XY: 149280 AN XY: 725496

Gnomad4 AFR exome AF: 0.0364

Gnomad4 AMR exome AF: 0.272

Gnomad4 ASJ exome AF: 0.143

Gnomad4 EAS exome AF: 0.190

Gnomad4 SAS exome AF: 0.0888

Gnomad4 FIN exome AF: 0.255

Gnomad4 NFE exome AF: 0.222

Gnomad4 OTH exome AF: 0.199

GnomAD4 genome AF: 0.172 AC: 26170 AN: 152088 Hom.: 2877 Cov.: 32 AF XY: 0.175 AC XY: 13023 AN XY: 74344

Gnomad4 AFR AF: 0.0428

Gnomad4 AMR AF: 0.243

Gnomad4 ASJ AF: 0.157

Gnomad4 EAS AF: 0.200

Gnomad4 SAS AF: 0.0924

Gnomad4 FIN AF: 0.268

Gnomad4 NFE AF: 0.223

Gnomad4 OTH AF: 0.204

Alfa AF: 0.210 Hom.: 8559

Bravo AF: 0.169

TwinsUK AF: 0.230 AC: 851

ALSPAC AF: 0.232 AC: 896

ESP6500AA AF: 0.0443 AC: 195

ESP6500EA AF: 0.218 AC: 1876

ExAC AF: 0.193 AC: 23436

Asia WGS AF: 0.118 AC: 410 AN: 3478

EpiCase AF: 0.221

EpiControl AF: 0.216

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	18
DANN	Benign	0.84
DEOGEN2	Benign	0.042	.;T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.50	T;T
MetaRNN	Benign	0.0048	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	.;L
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.30	T
Sift4G	Benign	0.47	T;T
Polyphen		0.030	.;B
Vest4		0.097
ClinPred		0.0080	T
GERP RS		3.5
Varity_R		0.050
gMVP		0.075

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: rs3748022; hg19: chr1-206669465; COSMIC: COSV65622766;