chr8-42271424-C-A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001556.3(IKBKB):​c.-64C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000025 in 1,241,378 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: IKBKB NM_001556.3 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.670
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.048465252).

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>A		5_prime_UTR	Exon 1 of 22	NP_001547.1	O14920-1
	IKBKB	NM_001242778.2		c.-146C>A		5_prime_UTR	Exon 1 of 21	NP_001229707.1	O14920-4
	IKBKB	NM_001190720.3		c.-133C>A		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>A		5_prime_UTR	Exon 1 of 22	ENSP00000430684.1	O14920-1
	IKBKB	ENST00000519735.5	TSL:1	n.107C>A		non_coding_transcript_exon	Exon 1 of 9
	IKBKB	ENST00000957021.1		c.-64C>A		5_prime_UTR	Exon 1 of 22	ENSP00000627080.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000250 AC: 31 AN: 1241378 Hom.: 0 Cov.: 24 AF XY: 0.0000276 AC XY: 17 AN XY: 616324

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000355 AC: 1 AN: 28144

American (AMR) AF: 0.00 AC: 0 AN: 34514

Ashkenazi Jewish (ASJ) AF: 0.0000429 AC: 1 AN: 23322

East Asian (EAS) AF: 0.00 AC: 0 AN: 33036

South Asian (SAS) AF: 0.00 AC: 0 AN: 76622

European-Finnish (FIN) AF: 0.0000349 AC: 1 AN: 28660

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3900

European-Non Finnish (NFE) AF: 0.0000271 AC: 26 AN: 961120

Other (OTH) AF: 0.0000384 AC: 2 AN: 52060

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	14
DANN	Benign	0.95
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.24	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-0.99	T
PhyloP100		0.67
PROVEAN	Benign	0.27	N
REVEL	Benign	0.066
Sift	Benign	1.0	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.091
MutPred		0.32		Loss of loop (P = 0.0288)
MVP		0.40
ClinPred		0.11	T
GERP RS		2.8
PromoterAI		0.12	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=86/14	polymorphism

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;