chr1-206474804-T-G

Variant names:

• chr1-206474804-T-G
• rs1953090
• NM_014002.4:c.229-61T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014002.4(IKBKE):​c.229-61T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.254 in 1,586,404 control chromosomes in the GnomAD database, including 52,698 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.25 (4840 hom., cov: 31)
  • Exomes 𝑓: 0.25 (47858 hom.)
• Consequence: IKBKE NM_014002.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.04
• Publications: 28 publications found

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]

MIR6769B (HGNC:50016): (microRNA 6769b) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.26 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IKBKE	NM_014002.4	c.229-61T>G		intron_variant	Intron 4 of 21	ENST00000581977.7	NP_054721.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IKBKE	ENST00000581977.7	c.229-61T>G		intron_variant	Intron 4 of 21	1	NM_014002.4	ENSP00000464030.1

Frequencies

GnomAD3 genomes AF: 0.249 AC: 37800 AN: 151960 Hom.: 4831 Cov.: 31

Gnomad AFR AF: 0.264

Gnomad AMI AF: 0.177

Gnomad AMR AF: 0.208

Gnomad ASJ AF: 0.156

Gnomad EAS AF: 0.139

Gnomad SAS AF: 0.265

Gnomad FIN AF: 0.291

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.256

Gnomad OTH AF: 0.220

GnomAD2 exomes AF: 0.239 AC: 55423 AN: 231880 AF XY: 0.240

Gnomad AFR exome AF: 0.258

Gnomad AMR exome AF: 0.225

Gnomad ASJ exome AF: 0.155

Gnomad EAS exome AF: 0.136

Gnomad FIN exome AF: 0.299

Gnomad NFE exome AF: 0.249

Gnomad OTH exome AF: 0.226

GnomAD4 exome AF: 0.255 AC: 365682 AN: 1434326 Hom.: 47858 Cov.: 30 AF XY: 0.254 AC XY: 180570 AN XY: 710422

African (AFR) AF: 0.254 AC: 8413 AN: 33076

American (AMR) AF: 0.218 AC: 9349 AN: 42964

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 3881 AN: 24612

East Asian (EAS) AF: 0.145 AC: 5697 AN: 39320

South Asian (SAS) AF: 0.252 AC: 20889 AN: 82740

European-Finnish (FIN) AF: 0.301 AC: 15513 AN: 51484

Middle Eastern (MID) AF: 0.131 AC: 732 AN: 5600

European-Non Finnish (NFE) AF: 0.262 AC: 287189 AN: 1095326

Other (OTH) AF: 0.237 AC: 14019 AN: 59204

GnomAD4 genome AF: 0.249 AC: 37832 AN: 152078 Hom.: 4840 Cov.: 31 AF XY: 0.248 AC XY: 18455 AN XY: 74332

African (AFR) AF: 0.265 AC: 10973 AN: 41480

American (AMR) AF: 0.208 AC: 3177 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 541 AN: 3470

East Asian (EAS) AF: 0.141 AC: 727 AN: 5174

South Asian (SAS) AF: 0.265 AC: 1282 AN: 4830

European-Finnish (FIN) AF: 0.291 AC: 3072 AN: 10572

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.256 AC: 17403 AN: 67948

Other (OTH) AF: 0.217 AC: 459 AN: 2116

Alfa AF: 0.229 Hom.: 5284

Bravo AF: 0.241

Asia WGS AF: 0.206 AC: 719 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.46
DANN	Benign	0.73
PhyloP100		-2.0

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

Other links and lift over

dbSNP: rs1953090; hg19: chr1-206648147; COSMIC: COSV65624738;