2-112836202-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000576.3(IL1B):c.28G>A(p.Glu10Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000744 in 1,613,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000077 (0 hom.)
• Consequence: IL1B NM_000576.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.686

Genes affected

IL1B (HGNC:5992): (interleukin 1 beta) The protein encoded by this gene is a member of the interleukin 1 cytokine family. This cytokine is produced by activated macrophages as a proprotein, which is proteolytically processed to its active form by caspase 1 (CASP1/ICE). This cytokine is an important mediator of the inflammatory response, and is involved in a variety of cellular activities, including cell proliferation, differentiation, and apoptosis. The induction of cyclooxygenase-2 (PTGS2/COX2) by this cytokine in the central nervous system (CNS) is found to contribute to inflammatory pain hypersensitivity. Similarly, IL-1B has been implicated in human osteoarthritis pathogenesis. Patients with severe Coronavirus Disease 2019 (COVID-19) present elevated levels of pro-inflammatory cytokines such as IL-1B in bronchial alveolar lavage fluid samples. The lung damage induced by the Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is to a large extent, a result of the inflammatory response promoted by cytokines such as IL-1B. This gene and eight other interleukin 1 family genes form a cytokine gene cluster on chromosome 2. [provided by RefSeq, Jul 2020]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.053975552).
• BS2: High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL1B	NM_000576.3	c.28G>A	p.Glu10Lys	missense_variant	2/7	ENST00000263341.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL1B	ENST00000263341.7	c.28G>A	p.Glu10Lys	missense_variant	2/7	1	NM_000576.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000115 AC: 29 AN: 251464 Hom.: 0 AF XY: 0.000177 AC XY: 24 AN XY: 135904

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 SAS exome AF: 0.000784

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000766 AC: 112 AN: 1461432 Hom.: 0 Cov.: 30 AF XY: 0.000111 AC XY: 81 AN XY: 727018

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000939

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152352 Hom.: 0 Cov.: 33 AF XY: 0.0000671 AC XY: 5 AN XY: 74492

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000900 Hom.: 0

Bravo AF: 0.0000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000123 AC: 15

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The IL1B p.Glu10Lys variant was not identified in the literature nor was it identified in ClinVar or Cosmic. The variant was identified in dbSNP (ID: rs376289593), LOVD 3.0 and in control databases in 29 of 251464 chromosomes at a frequency of 0.000115 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 24 of 30616 chromosomes (freq: 0.000784), Other in 2 of 6138 chromosomes (freq: 0.000326) and European (non-Finnish) in 3 of 113746 chromosomes (freq: 0.000026), while the variant was not observed in the African, Latino, Ashkenazi Jewish, East Asian, and European (Finnish) populations. The p.Glu10 residue is not conserved in mammals and four out of five computational analyses (SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.16
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Benign	0.35	T;T;.;T
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.082
FATHMM_MKL	Benign	0.13	N
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.054	T;T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.2	M;.;.;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.6	N;N;D;D
REVEL	Uncertain	0.31
Sift	Benign	0.057	T;D;D;D
Sift4G	Benign	0.096	T;D;.;D
Polyphen		1.0	D;.;.;.
Vest4		0.23
MVP		0.72
MPC		1.3
ClinPred		0.33	T
GERP RS		4.7
Varity_R		0.22
gMVP		0.40

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

Publications

LitVar

Other links and lift over

dbSNP: rs376289593; hg19: chr2-113593779;