Genetic Variant NM_001556.3:c.-40T>C (chr8-42271448-T-C) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001556.3(IKBKB):c.-40T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00279 in 946,232 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.0022 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0029 ( 33 hom. )

Consequence

IKBKB
NM_001556.3 5_prime_UTR

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.436

Variant links:

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]

IKBKB links:

IKBKB-DT (HGNC:55254): (IKBKB divergent transcript)

IKBKB-DT links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 8-42271448-T-C is Benign according to our data. Variant chr8-42271448-T-C is described in ClinVar as [Benign]. Clinvar id is 3042121.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00221 (295/133366) while in subpopulation SAS AF= 0.0245 (92/3758). AF 95% confidence interval is 0.0204. There are 3 homozygotes in gnomad4. There are 158 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IKBKB	NM_001556.3 link	c.-40T>C		5_prime_UTR_variant	Exon 1 of 22	ENST00000520810.6	NP_001547.1	O14920-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IKBKB	ENST00000520810 link	c.-40T>C		5_prime_UTR_variant	Exon 1 of 22	1	NM_001556.3	ENSP00000430684.1		O14920-1

Frequencies

GnomAD3 genomes

AF:

0.00223

AC:

297

AN:

133296

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000574

Gnomad ASJ

AF:

0.000951

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0247

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0267

Gnomad NFE

AF:

0.00123

Gnomad OTH

AF:

0.00156

GnomAD3 exomes

AF:

0.00425

AC:

506

AN:

119094

Hom.:

AF XY:

0.00560

AC XY:

367

AN XY:

65578

show subpopulations

Gnomad AFR exome

AF:

0.00246

Gnomad AMR exome

AF:

0.000382

Gnomad ASJ exome

AF:

0.000806

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0195

Gnomad FIN exome

AF:

0.000200

Gnomad NFE exome

AF:

0.00116

Gnomad OTH exome

AF:

0.00244

GnomAD4 exome

AF:

0.00288

AC:

2345

AN:

812866

Hom.:

Cov.:

AF XY:

0.00381

AC XY:

1563

AN XY:

410528

show subpopulations

Gnomad4 AFR exome

AF:

0.00404

Gnomad4 AMR exome

AF:

0.000705

Gnomad4 ASJ exome

AF:

0.000676

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0201

Gnomad4 FIN exome

AF:

0.000135

Gnomad4 NFE exome

AF:

0.00118

Gnomad4 OTH exome

AF:

0.00282

GnomAD4 genome

AF:

0.00221

AC:

295

AN:

133366

Hom.:

Cov.:

AF XY:

0.00242

AC XY:

158

AN XY:

65202

show subpopulations

Gnomad4 AFR

AF:

0.00289

Gnomad4 AMR

AF:

0.000573

Gnomad4 ASJ

AF:

0.000951

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0245

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00123

Gnomad4 OTH

AF:

0.00155

Alfa

AF:

0.00210

Hom.:

Asia WGS

AF:

0.00780

AC:

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

IKBKB-related disorder

Benign:1

Oct 31, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

6.1

DANN

Benign

0.58

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over