2-113120071-T-G

Position:

• chr2-113120071-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000259206.9(IL1RN):​c.16T>G​(p.Leu6Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,461,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L6F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: IL1RN ENST00000259206.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0230

Genes affected

IL1RN (HGNC:6000): (interleukin 1 receptor antagonist) The protein encoded by this gene is a member of the interleukin 1 cytokine family. This protein inhibits the activities of interleukin 1, alpha (IL1A) and interleukin 1, beta (IL1B), and modulates a variety of interleukin 1 related immune and inflammatory responses, particularly in the acute phase of infection and inflammation. This gene and five other closely related cytokine genes form a gene cluster spanning approximately 400 kb on chromosome 2. A polymorphism of this gene is reported to be associated with increased risk of osteoporotic fractures and gastric cancer. Several alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Aug 2020]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05456847).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL1RN	NM_173841.3	c.16T>G	p.Leu6Val	missense_variant	2/6		NP_776213.1
IL1RN	NM_001318914.2	c.-267T>G		5_prime_UTR_variant	2/7		NP_001305843.1
IL1RN	XM_011511121.2	c.-267T>G		5_prime_UTR_variant	4/9		XP_011509423.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL1RN	ENST00000259206.9	c.16T>G	p.Leu6Val	missense_variant	2/6	1		ENSP00000259206
IL1RN	ENST00000354115.6	c.10+2043T>G		intron_variant		1		ENSP00000329072	A1
IL1RN	ENST00000361779.7	c.-209-1377T>G		intron_variant		1		ENSP00000354816

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1461000 Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8 AN XY: 726856

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Sterile multifocal osteomyelitis with periostitis and pustulosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 20, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with IL1RN-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with valine at codon 6 of the IL1RN protein (p.Leu6Val). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and valine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.86
DANN	Benign	0.80
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0031	N
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.054
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.065
MutPred		0.14		Gain of loop (P = 0.069);
MVP		0.14
MPC		0.051
ClinPred		0.92	D
GERP RS		-0.76
gMVP		0.26

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1686715665; hg19: chr2-113877648;