rs56230731

Variant names:

• chr8-42316862-G-A
• rs56230731
• NM_001556.3:c.1083G>A

Your query was ambiguous. Multiple possible variants found:

• chr8-42316862-G-A
• chr8-42316862-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001556.3(IKBKB):​c.1083G>A​(p.Leu361Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.0128 in 1,614,106 control chromosomes in the GnomAD database, including 185 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0098 (4 hom., cov: 32)
  • Exomes 𝑓: 0.013 (181 hom.)
• Consequence: IKBKB NM_001556.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.06
• Publications: 6 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 Gene-Disease associations (from GenCC):

• severe combined immunodeficiency due to IKK2 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• immunodeficiency 15a

  Inheritance: AD, AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 8-42316862-G-A is Benign according to our data. Variant chr8-42316862-G-A is described in ClinVar as Benign. ClinVar VariationId is 474788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00977 (1488/152284) while in subpopulation NFE AF = 0.0169 (1150/68030). AF 95% confidence interval is 0.0161. There are 4 homozygotes in GnomAd4. There are 668 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.1083G>A	p.Leu361Leu	synonymous	Exon 11 of 22	NP_001547.1	O14920-1
	IKBKB	NM_001242778.2		c.906G>A	p.Leu302Leu	synonymous	Exon 10 of 21	NP_001229707.1	O14920-4
	IKBKB	NM_001190720.3		c.891G>A	p.Leu297Leu	synonymous	Exon 10 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.1083G>A	p.Leu361Leu	synonymous	Exon 11 of 22	ENSP00000430684.1	O14920-1
	IKBKB	ENST00000523517.5	TSL:1	n.1083G>A		non_coding_transcript_exon	Exon 10 of 21	ENSP00000430114.1	E5RGW5
	IKBKB	ENST00000957021.1		c.1083G>A	p.Leu361Leu	synonymous	Exon 11 of 22	ENSP00000627080.1

Frequencies

GnomAD3 genomes AF: 0.00978 AC: 1488 AN: 152166 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00251

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0137

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0169

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.00925 AC: 2323 AN: 251040 AF XY: 0.00885

Gnomad AFR exome AF: 0.00271

Gnomad AMR exome AF: 0.00234

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0153

Gnomad NFE exome AF: 0.0158

Gnomad OTH exome AF: 0.00915

GnomAD4 exome AF: 0.0131 AC: 19185 AN: 1461822 Hom.: 181 Cov.: 31 AF XY: 0.0126 AC XY: 9176 AN XY: 727214

African (AFR) AF: 0.00212 AC: 71 AN: 33480

American (AMR) AF: 0.00235 AC: 105 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00203 AC: 53 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86248

European-Finnish (FIN) AF: 0.0158 AC: 843 AN: 53396

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0157 AC: 17510 AN: 1111986

Other (OTH) AF: 0.00985 AC: 595 AN: 60390

GnomAD4 genome AF: 0.00977 AC: 1488 AN: 152284 Hom.: 4 Cov.: 32 AF XY: 0.00897 AC XY: 668 AN XY: 74458

African (AFR) AF: 0.00250 AC: 104 AN: 41556

American (AMR) AF: 0.00419 AC: 64 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.0137 AC: 145 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0169 AC: 1150 AN: 68030

Other (OTH) AF: 0.00710 AC: 15 AN: 2112

Alfa AF: 0.0136 Hom.: 48

Bravo AF: 0.00875

Asia WGS AF: 0.000866 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Severe combined immunodeficiency due to IKK2 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	5.2
DANN	Benign	0.41
PhyloP100		4.1
Mutation Taster		=96/4	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: rs56230731; hg19: chr8-42174380;