2-102340781-A-G

Position:

• chr2-102340781-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_016232.5(IL1RL1):​c.563A>G​(p.Asn188Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000696 in 1,437,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: IL1RL1 NM_016232.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.07

Genes affected

IL1RL1 (HGNC:5998): (interleukin 1 receptor like 1) The protein encoded by this gene is a member of the interleukin 1 receptor family. Studies of the similar gene in mouse suggested that this receptor can be induced by proinflammatory stimuli, and may be involved in the function of helper T cells. This gene, interleukin 1 receptor, type I (IL1R1), interleukin 1 receptor, type II (IL1R2) and interleukin 1 receptor-like 2 (IL1RL2) form a cytokine receptor gene cluster in a region mapped to chromosome 2q12. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jul 2008]

IL18R1 (HGNC:5988): (interleukin 18 receptor 1) The protein encoded by this gene is a cytokine receptor that belongs to the interleukin 1 receptor family. This receptor specifically binds interleukin 18 (IL18), and is essential for IL18 mediated signal transduction. IFN-alpha and IL12 are reported to induce the expression of this receptor in NK and T cells. This gene along with four other members of the interleukin 1 receptor family, including IL1R2, IL1R1, ILRL2 (IL-1Rrp2), and IL1RL1 (T1/ST2), form a gene cluster on chromosome 2q. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33648342).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL1RL1	NM_016232.5	c.563A>G	p.Asn188Ser	missense_variant	5/11	ENST00000233954.6	NP_057316.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL1RL1	ENST00000233954.6	c.563A>G	p.Asn188Ser	missense_variant	5/11	1	NM_016232.5	ENSP00000233954.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1437048 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 715104

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: 9.05e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 20, 2024

The c.563A>G (p.N188S) alteration is located in exon 5 (coding exon 4) of the IL1RL1 gene. This alteration results from a A to G substitution at nucleotide position 563, causing the asparagine (N) at amino acid position 188 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	.;T;.;T
Eigen	Benign	-0.093
Eigen_PC	Benign	-0.0038
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.71	T;T;T;T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.34	T;T;T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.5	.;M;M;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.7	D;N;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.10	T;T;T;T
Sift4G	Benign	0.067	T;T;T;T
Polyphen		0.43, 0.37	.;B;B;.
Vest4		0.32
MutPred		0.67		.;Gain of glycosylation at N188 (P = 0.0352);Gain of glycosylation at N188 (P = 0.0352);Gain of glycosylation at N188 (P = 0.0352);
MVP		0.85
MPC		0.030
ClinPred		0.76	D
GERP RS		5.4
Varity_R		0.13
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1677527302; hg19: chr2-102957241;