8-42271424-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001556.3(IKBKB):c.-64C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0186 in 1,392,528 control chromosomes in the GnomAD database, including 664 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (145 hom., cov: 32)
  • Exomes 𝑓: 0.018 (519 hom.)
• Consequence: IKBKB NM_001556.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.670

Genes affected

IKBKB (HGNC:5960): (inhibitor of nuclear factor kappa B kinase subunit beta) The protein encoded by this gene phosphorylates the inhibitor in the inhibitor/NF-kappa-B complex, causing dissociation of the inhibitor and activation of NF-kappa-B. The encoded protein itself is found in a complex of proteins. Several transcript variants, some protein-coding and some not, have been found for this gene. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 8-42271424-C-T is Benign according to our data. Variant chr8-42271424-C-T is described in ClinVar as [Benign]. Clinvar id is 1245244.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IKBKB	NM_001556.3	c.-64C>T		5_prime_UTR_variant	1/22	ENST00000520810.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IKBKB	ENST00000520810.6	c.-64C>T		5_prime_UTR_variant	1/22	1	NM_001556.3	P1

Frequencies

GnomAD3 genomes AF: 0.0213 AC: 3209 AN: 150776 Hom.: 143 Cov.: 32

Gnomad AFR AF: 0.00582

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.0145

Gnomad EAS AF: 0.000598

Gnomad SAS AF: 0.0132

Gnomad FIN AF: 0.0149

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0154

Gnomad OTH AF: 0.0159

GnomAD3 exomes AF: 0.0380 AC: 4782 AN: 125808 Hom.: 276 AF XY: 0.0318 AC XY: 2199 AN XY: 69148

Gnomad AFR exome AF: 0.00335

Gnomad AMR exome AF: 0.143

Gnomad ASJ exome AF: 0.0136

Gnomad EAS exome AF: 0.000101

Gnomad SAS exome AF: 0.0148

Gnomad FIN exome AF: 0.0133

Gnomad NFE exome AF: 0.0150

Gnomad OTH exome AF: 0.0303

GnomAD4 exome AF: 0.0183 AC: 22689 AN: 1241638 Hom.: 519 Cov.: 24 AF XY: 0.0179 AC XY: 11045 AN XY: 616442

Gnomad4 AFR exome AF: 0.00345

Gnomad4 AMR exome AF: 0.138

Gnomad4 ASJ exome AF: 0.0143

Gnomad4 EAS exome AF: 0.0000908

Gnomad4 SAS exome AF: 0.0152

Gnomad4 FIN exome AF: 0.0170

Gnomad4 NFE exome AF: 0.0156

Gnomad4 OTH exome AF: 0.0154

GnomAD4 genome AF: 0.0214 AC: 3223 AN: 150890 Hom.: 145 Cov.: 32 AF XY: 0.0234 AC XY: 1726 AN XY: 73770

Gnomad4 AFR AF: 0.00581

Gnomad4 AMR AF: 0.108

Gnomad4 ASJ AF: 0.0145

Gnomad4 EAS AF: 0.000599

Gnomad4 SAS AF: 0.0130

Gnomad4 FIN AF: 0.0149

Gnomad4 NFE AF: 0.0154

Gnomad4 OTH AF: 0.0157

Alfa AF: 0.0203 Hom.: 8

Bravo AF: 0.0248

Asia WGS AF: 0.00809 AC: 28 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 24% of patients studied by a panel of primary immunodeficiencies. Number of patients: 21. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
Cadd	Benign	14
Dann	Uncertain	0.98
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs12545246; hg19: chr8-42128942; COSMIC: COSV104646985; COSMIC: COSV104646985;