chr2-112833537-G-A

Variant names:

• chr2-112833537-G-A
• rs140794289
• NM_000576.3:c.138C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000576.3(IL1B):​c.138C>T​(p.Gly46Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00167 in 1,614,032 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (33 hom.)
• Consequence: IL1B NM_000576.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.297

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

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 2-112833537-G-A is Benign according to our data. Variant chr2-112833537-G-A is described in ClinVar as [Benign]. Clinvar id is 780097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.297 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00141 (215/152254) while in subpopulation EAS AF = 0.0257 (133/5178). AF 95% confidence interval is 0.0221. There are 4 homozygotes in GnomAd4. There are 135 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High AC in GnomAd4 at 215 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL1B	NM_000576.3	c.138C>T	p.Gly46Gly	synonymous_variant	Exon 4 of 7	ENST00000263341.7	NP_000567.1
IL1B	XM_047444175.1	c.-354C>T		upstream_gene_variant			XP_047300131.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL1B	ENST00000263341.7	c.138C>T	p.Gly46Gly	synonymous_variant	Exon 4 of 7	1	NM_000576.3	ENSP00000263341.2

Frequencies

GnomAD3 genomes AF: 0.00142 AC: 216 AN: 152136 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0256

Gnomad SAS AF: 0.0151

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00390 AC: 981 AN: 251260 AF XY: 0.00423

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0284

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000158

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00169 AC: 2475 AN: 1461778 Hom.: 33 Cov.: 32 AF XY: 0.00202 AC XY: 1468 AN XY: 727180

Gnomad4 AFR exome AF: 0.0000299 AC: 1 AN: 33480

Gnomad4 AMR exome AF: 0.000201 AC: 9 AN: 44722

Gnomad4 ASJ exome AF: 0.0000383 AC: 1 AN: 26136

Gnomad4 EAS exome AF: 0.0257 AC: 1022 AN: 39700

Gnomad4 SAS exome AF: 0.0139 AC: 1202 AN: 86258

Gnomad4 FIN exome AF: 0.0000188 AC: 1 AN: 53324

Gnomad4 NFE exome AF: 0.0000719 AC: 80 AN: 1112000

Gnomad4 Remaining exome AF: 0.00257 AC: 155 AN: 60390

GnomAD4 genome AF: 0.00141 AC: 215 AN: 152254 Hom.: 4 Cov.: 32 AF XY: 0.00181 AC XY: 135 AN XY: 74448

Gnomad4 AFR AF: 0.0000481 AC: 0.0000481394 AN: 0.0000481394

Gnomad4 AMR AF: 0.000262 AC: 0.00026154 AN: 0.00026154

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.0257 AC: 0.0256856 AN: 0.0256856

Gnomad4 SAS AF: 0.0149 AC: 0.0149378 AN: 0.0149378

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000588 AC: 0.000058801 AN: 0.000058801

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000259 Hom.: 0

Bravo AF: 0.00131

Asia WGS AF: 0.0130 AC: 44 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 21, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.9
DANN	Benign	0.83
Mutation Taster		=100/0	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

Publications

LitVar

Other links and lift over

dbSNP: rs140794289; hg19: chr2-113591114;