2-112833585-G-A

Position:

• chr2-112833585-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000576.3(IL1B):​c.100-10C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00755 in 1,613,266 control chromosomes in the GnomAD database, including 122 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0077 (114 hom.)
• Consequence: IL1B NM_000576.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003023
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.694

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-112833585-G-A is Benign according to our data. Variant chr2-112833585-G-A is described in ClinVar as [Benign]. Clinvar id is 772847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00584 (889/152322) while in subpopulation SAS AF= 0.0292 (141/4826). AF 95% confidence interval is 0.0253. There are 8 homozygotes in gnomad4. There are 437 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 889 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL1B	NM_000576.3	c.100-10C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000263341.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL1B	ENST00000263341.7	c.100-10C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000576.3	P1

Frequencies

GnomAD3 genomes AF: 0.00585 AC: 890 AN: 152204 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00563

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0292

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00744

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.00895 AC: 2241 AN: 250444 Hom.: 41 AF XY: 0.0107 AC XY: 1451 AN XY: 135330

Gnomad AFR exome AF: 0.00130

Gnomad AMR exome AF: 0.00393

Gnomad ASJ exome AF: 0.0214

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.0309

Gnomad FIN exome AF: 0.000804

Gnomad NFE exome AF: 0.00735

Gnomad OTH exome AF: 0.0111

GnomAD4 exome AF: 0.00773 AC: 11291 AN: 1460944 Hom.: 114 Cov.: 31 AF XY: 0.00867 AC XY: 6302 AN XY: 726718

Gnomad4 AFR exome AF: 0.00114

Gnomad4 AMR exome AF: 0.00479

Gnomad4 ASJ exome AF: 0.0202

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0318

Gnomad4 FIN exome AF: 0.000812

Gnomad4 NFE exome AF: 0.00629

Gnomad4 OTH exome AF: 0.00908

GnomAD4 genome AF: 0.00584 AC: 889 AN: 152322 Hom.: 8 Cov.: 32 AF XY: 0.00587 AC XY: 437 AN XY: 74484

Gnomad4 AFR AF: 0.00118

Gnomad4 AMR AF: 0.00562

Gnomad4 ASJ AF: 0.0190

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0292

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.00744

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00459 Hom.: 0

Bravo AF: 0.00565

Asia WGS AF: 0.00982 AC: 34 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 14, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.0
DANN	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000030
dbscSNV1_RF	Benign	0.0020
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: rs3917359; hg19: chr2-113591162;