8-42271424-C-T

Variant names:

• chr8-42271424-C-T
• rs12545246
• NM_001556.3:c.-64C>T

Variant summary

Our verdict is Benign. The variant received -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:3
• Conservation: PhyloP100: 0.670
• Publications: 3 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IKBKB	NM_001556.3	MANE Select	c.-64C>T		5_prime_UTR	Exon 1 of 22	NP_001547.1	O14920-1
	IKBKB	NM_001242778.2		c.-146C>T		5_prime_UTR	Exon 1 of 21	NP_001229707.1	O14920-4
	IKBKB	NM_001190720.3		c.-133C>T		5_prime_UTR	Exon 1 of 21	NP_001177649.2	A0A499FJS7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IKBKB	ENST00000520810.6	TSL:1 MANE Select	c.-64C>T		5_prime_UTR	Exon 1 of 22	ENSP00000430684.1	O14920-1
	IKBKB	ENST00000519735.5	TSL:1	n.107C>T		non_coding_transcript_exon	Exon 1 of 9
	IKBKB	ENST00000957021.1		c.-64C>T		5_prime_UTR	Exon 1 of 22	ENSP00000627080.1

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

GnomAD2 exomes AF: 0.0380 AC: 4782 AN: 125808 AF XY: 0.0318

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 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

African (AFR) AF: 0.00345 AC: 97 AN: 28148

American (AMR) AF: 0.138 AC: 4769 AN: 34508

Ashkenazi Jewish (ASJ) AF: 0.0143 AC: 334 AN: 23324

East Asian (EAS) AF: 0.0000908 AC: 3 AN: 33038

South Asian (SAS) AF: 0.0152 AC: 1165 AN: 76626

European-Finnish (FIN) AF: 0.0170 AC: 487 AN: 28670

Middle Eastern (MID) AF: 0.00666 AC: 26 AN: 3904

European-Non Finnish (NFE) AF: 0.0156 AC: 15004 AN: 961348

Other (OTH) AF: 0.0154 AC: 804 AN: 52072

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

African (AFR) AF: 0.00581 AC: 240 AN: 41330

American (AMR) AF: 0.108 AC: 1639 AN: 15202

Ashkenazi Jewish (ASJ) AF: 0.0145 AC: 50 AN: 3454

East Asian (EAS) AF: 0.000599 AC: 3 AN: 5006

South Asian (SAS) AF: 0.0130 AC: 61 AN: 4700

European-Finnish (FIN) AF: 0.0149 AC: 153 AN: 10240

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0154 AC: 1043 AN: 67660

Other (OTH) AF: 0.0157 AC: 33 AN: 2096

Alfa AF: 0.0203 Hom.: 8

Bravo AF: 0.0248

Asia WGS AF: 0.00809 AC: 28 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	14
DANN	Uncertain	0.98
PhyloP100		0.67
PromoterAI		-0.032	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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