chr8-42271381-G-C

Variant names:

• chr8-42271381-G-C
• rs201028246
• NM_001556.3:c.-107G>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001556.3(IKBKB):​c.-107G>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 0.00123 in 1,510,110 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00091 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (3 hom.)
• Consequence: IKBKB NM_001556.3 5_prime_UTR
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.201
• Publications: 5 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046812594).
• BP6: Variant 8-42271381-G-C is Benign according to our data. Variant chr8-42271381-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3039446.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000913 (139/152306) while in subpopulation SAS AF = 0.0029 (14/4830). AF 95% confidence interval is 0.00175. There are 0 homozygotes in GnomAd4. There are 68 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IKBKB	NM_001556.3	MANE Select	c.-107G>C		5_prime_UTR	Exon 1 of 22	NP_001547.1	O14920-1
	IKBKB	NM_001242778.2		c.-189G>C		5_prime_UTR	Exon 1 of 21	NP_001229707.1	O14920-4
	IKBKB	NM_001190720.3		c.-176G>C		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.-107G>C		5_prime_UTR	Exon 1 of 22	ENSP00000430684.1	O14920-1
	IKBKB	ENST00000519735.5	TSL:1	n.64G>C		non_coding_transcript_exon	Exon 1 of 9
	IKBKB	ENST00000957021.1		c.-107G>C		5_prime_UTR	Exon 1 of 22	ENSP00000627080.1

Frequencies

GnomAD3 genomes AF: 0.000920 AC: 140 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00143

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00129 AC: 169 AN: 131282 AF XY: 0.00147

Gnomad AFR exome AF: 0.000676

Gnomad AMR exome AF: 0.0000823

Gnomad ASJ exome AF: 0.00222

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.00140

Gnomad OTH exome AF: 0.000989

GnomAD4 exome AF: 0.00127 AC: 1718 AN: 1357804 Hom.: 3 Cov.: 26 AF XY: 0.00134 AC XY: 902 AN XY: 671412

African (AFR) AF: 0.000452 AC: 14 AN: 30962

American (AMR) AF: 0.0000843 AC: 3 AN: 35608

Ashkenazi Jewish (ASJ) AF: 0.00244 AC: 61 AN: 24992

East Asian (EAS) AF: 0.00 AC: 0 AN: 35520

South Asian (SAS) AF: 0.00310 AC: 244 AN: 78738

European-Finnish (FIN) AF: 0.000359 AC: 12 AN: 33446

Middle Eastern (MID) AF: 0.00186 AC: 10 AN: 5362

European-Non Finnish (NFE) AF: 0.00119 AC: 1258 AN: 1056296

Other (OTH) AF: 0.00204 AC: 116 AN: 56880

GnomAD4 genome AF: 0.000913 AC: 139 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.000913 AC XY: 68 AN XY: 74476

African (AFR) AF: 0.000289 AC: 12 AN: 41582

American (AMR) AF: 0.0000653 AC: 1 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4830

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00143 AC: 97 AN: 68010

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00122 Hom.: 0

Bravo AF: 0.000793

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ExAC AF: 0.00147 AC: 24

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	IKBKB-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	5.1
DANN	Benign	0.68
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.36	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.20
PROVEAN	Benign	0.060	N
REVEL	Benign	0.071
Sift	Benign	0.85	T
Polyphen		0.0010	B
Vest4		0.083
MVP		0.35
ClinPred		0.0015	T
GERP RS		-0.29
PromoterAI		-0.12	Neutral
Mutation Taster		=97/3	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: rs201028246; hg19: chr8-42128899;