Genetic Variant IKBKB:c.-19+8C>T (chr8-42271477-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001556.3(IKBKB):c.-19+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00042 in 1,188,000 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00081 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00036 ( 2 hom. )

Consequence

IKBKB
NM_001556.3 splice_region, intron

Scores

Splicing: ADA: 0.00009614

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: -0.0800

Publications

0 publications found

Variant links:

COSMIC-nc: COSV107421993

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 was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP6

Variant 8-42271477-C-T is Benign according to our data. Variant chr8-42271477-C-T is described in ClinVar as Benign. ClinVar VariationId is 3037325.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000808 (123/152252) while in subpopulation NFE AF = 0.000677 (46/67978). AF 95% confidence interval is 0.000521. There are 0 homozygotes in GnomAd4. There are 84 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001556.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
IKBKB	NM_001556.3	MANE Select	c.-19+8C>T	splice_region intron	N/A	NP_001547.1	O14920-1
IKBKB	NM_001242778.2		c.-101+8C>T	splice_region intron	N/A	NP_001229707.1	O14920-4
IKBKB	NM_001190720.3		c.-88+8C>T	splice_region intron	N/A	NP_001177649.2	A0A499FJS7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
IKBKB	ENST00000520810.6	TSL:1 MANE Select	c.-19+8C>T	splice_region intron	N/A	ENSP00000430684.1	O14920-1
IKBKB	ENST00000519735.5	TSL:1	n.152+8C>T	splice_region intron	N/A
IKBKB	ENST00000870193.1		c.-275C>T	5_prime_UTR	Exon 1 of 22	ENSP00000540252.1

Frequencies

GnomAD3 genomes

AF:

0.000808

AC:

123

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00668

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000677

Gnomad OTH

AF:

0.000958

GnomAD2 exomes

AF:

0.000443

AC:

AN:

85828

AF XY:

0.000532

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00796

Gnomad NFE exome

AF:

0.000332

Gnomad OTH exome

AF:

0.000356

GnomAD4 exome

AF:

0.000363

AC:

376

AN:

1035748

Hom.:

Cov.:

AF XY:

0.000363

AC XY:

189

AN XY:

520258

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22690

American (AMR)

AF:

0.00

AC:

AN:

30876

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20512

East Asian (EAS)

AF:

0.0000318

AC:

AN:

31402

South Asian (SAS)

AF:

0.00

AC:

AN:

67296

European-Finnish (FIN)

AF:

0.00653

AC:

209

AN:

32008

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3356

European-Non Finnish (NFE)

AF:

0.000180

AC:

141

AN:

781626

Other (OTH)

AF:

0.000544

AC:

AN:

45982

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000808

AC:

123

AN:

152252

Hom.:

Cov.:

AF XY:

0.00113

AC XY:

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41570

American (AMR)

AF:

0.0000654

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000387

AC:

AN:

5172

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00668

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000677

AC:

AN:

67978

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00164

Hom.:

Bravo

AF:

0.0000982

Asia WGS

AF:

0.00202

AC:

AN:

3476

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

IKBKB-related disorder (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

9.0

(source)

DANN

Benign

0.88

PhyloP100

-0.080

PromoterAI

-0.081

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000096

dbscSNV1_RF

Benign

0.0020

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over