chr2-112832890-C-T

Variant names:

• chr2-112832890-C-T
• rs1143633
• NM_000576.3:c.302-64G>A

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_Strong

The NM_000576.3(IL1B):c.302-64G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.343 (AC=537,783) in the gnomAD database across 1,568,952 control chromosomes, including 95,129 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.568. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.31 (7669 hom., cov: 32)
  • Exomes 𝑓: 0.35 (87460 hom.)
• Consequence: IL1B NM_000576.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.479
• Publications: 135 publications found

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]

IL1B Gene-Disease associations (from GenCC):

• hereditary diffuse gastric adenocarcinoma

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000299339 (HGNC:):

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.5679 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000576.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	IL1B NM_000576.3	MANE Select	c.302-64G>A	intron	Intron 4 of 6	Prot: NP_000567.1 UniProt:

IL1B NM_000576.3

MANE Select

HGVSc / HGVSpc.302-64G>A

Exon rankIntron 4 of 6

intron

Prot: NP_000567.1UniProt: P01584

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	IL1B ENST00000263341.7	TSL:1MANE Select	c.302-64G>A	intron	Intron 4 of 6	Prot: ENSP00000263341.2 UniProt:
	IL1B ENST00000491056.5	TSL:1	n.1109-64G>A	intron	Intron 3 of 5	Prot:
	IL1B ENST00000418817.5	TSL:3	c.302-64G>A	intron	Intron 4 of 4	Prot: ENSP00000407219.1 UniProt:

IL1B ENST00000263341.7

TSL:1MANE Select

HGVSc / HGVSpc.302-64G>A

Exon rankIntron 4 of 6

intron

Prot: ENSP00000263341.2UniProt: P01584

IL1B ENST00000491056.5

TSL:1

HGVSc / HGVSpn.1109-64G>A

Exon rankIntron 3 of 5

intron

Prot:

IL1B ENST00000418817.5

TSL:3

HGVSc / HGVSpc.302-64G>A

Exon rankIntron 4 of 4

intron

Prot: ENSP00000407219.1UniProt: C9JWV2

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.306	AC:46546	Hom:7670	AN:151916	Cov:32
GnomAD4 exome	AF: 0.347	AC:491220	Hom:87460	AN:1416918	Cov:24
GnomAD4 genome	AF: 0.306	AC:46563	Hom:7669	AN:152034	Cov:32
TOPMed (Bravo)	AF: 0.308	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.342	AC:212976	Hom:37314	AN:622154	Cov:
Local & regional cohorts 9 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.333	AC:780	Hom:122	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.566	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.350	AC:105	Hom:	AN:300	Cov:
GenomeAsia100K	AF: 0.339	AC:1180	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.587	AC:4247	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.193	AC:34	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.582	AC:71370	Hom:20814	AN:122698	Cov:
UK10K	AF: 0.362	AC:2741	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.565	AC:5063	Hom:1450	AN:8960	Cov:

Showing 14 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.290	22373	77180	0.290	40114	138320

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	4.7
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.5
DANN	Benign	0.55
GPN-Star LLR	N/A	0.0
GPN-Star score	N/A	0.0
Mutation Taster	N/A	100/0	polymorphism (auto)
PhyloP100	Benign	-0.48

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs1143633;

hg19: chr2-113590467;

COSMIC: COSV54521294;

COSMIC: COSV54521294;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar