chr2-112832890-C-G

Variant names:

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

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-2 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -2 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_Strong

The NM_000576.3(IL1B):c.302-64G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. 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: not found (cov: 32)
• 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: Likely_benign. The variant received -2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AR/unknown gene) — PM2; Absent from gnomAD at well-covered site (MOI: unknown) (threshold 0.001) — PM2 moderate.
	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).

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>C	intron	Intron 4 of 6	Prot: NP_000567.1 UniProt:

IL1B NM_000576.3

MANE Select

HGVSc / HGVSpc.302-64G>C

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>C	intron	Intron 4 of 6	Prot: ENSP00000263341.2 UniProt:
	IL1B ENST00000491056.5	TSL:1	n.1109-64G>C	intron	Intron 3 of 5	Prot:
	IL1B ENST00000418817.5	TSL:3	c.302-64G>C	intron	Intron 4 of 4	Prot: ENSP00000407219.1 UniProt:

IL1B ENST00000263341.7

TSL:1MANE Select

HGVSc / HGVSpc.302-64G>C

Exon rankIntron 4 of 6

intron

Prot: ENSP00000263341.2UniProt: P01584

IL1B ENST00000491056.5

TSL:1

HGVSc / HGVSpn.1109-64G>C

Exon rankIntron 3 of 5

intron

Prot:

IL1B ENST00000418817.5

TSL:3

HGVSc / HGVSpc.302-64G>C

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 4 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:24
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:37314	AN:622154	Cov:

Showing 4 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	5.2
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.5
DANN	Benign	0.37
GPN-Star LLR	N/A	0.18
GPN-Star score	N/A	-0.18
PhyloP100	Benign	-0.48

Showing 7 of 7 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;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar