2-102342258-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_016232.5(IL1RL1):c.646G>A(p.Ala216Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00381 in 1,611,566 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (21 hom.)
• Consequence: IL1RL1 NM_016232.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.229

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009360373).
• BP6: Variant 2-102342258-G-A is Benign according to our data. Variant chr2-102342258-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 711194.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL1RL1	NM_016232.5	c.646G>A	p.Ala216Thr	missense_variant	6/11	ENST00000233954.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL1RL1	ENST00000233954.6	c.646G>A	p.Ala216Thr	missense_variant	6/11	1	NM_016232.5	P1

Frequencies

GnomAD3 genomes AF: 0.00297 AC: 452 AN: 152034 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00459

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00227

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00447

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00416 AC: 1043 AN: 250938 Hom.: 5 AF XY: 0.00384 AC XY: 521 AN XY: 135678

Gnomad AFR exome AF: 0.000494

Gnomad AMR exome AF: 0.0123

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00248

Gnomad FIN exome AF: 0.00310

Gnomad NFE exome AF: 0.00397

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00390 AC: 5687 AN: 1459414 Hom.: 21 Cov.: 28 AF XY: 0.00384 AC XY: 2789 AN XY: 726176

Gnomad4 AFR exome AF: 0.000449

Gnomad4 AMR exome AF: 0.0109

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.00291

Gnomad4 FIN exome AF: 0.00379

Gnomad4 NFE exome AF: 0.00405

Gnomad4 OTH exome AF: 0.00357

GnomAD4 genome AF: 0.00297 AC: 452 AN: 152152 Hom.: 1 Cov.: 32 AF XY: 0.00258 AC XY: 192 AN XY: 74398

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.00452

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.000831

Gnomad4 FIN AF: 0.00227

Gnomad4 NFE AF: 0.00447

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00363 Hom.: 2

Bravo AF: 0.00326

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00372 AC: 32

ExAC AF: 0.00394 AC: 478

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00388

EpiControl AF: 0.00350

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	IL1RL1: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Aug 15, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	3.8
Dann	Benign	0.72
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.69	T;T;T;T
MetaRNN	Benign	0.0094	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.2	N;N;N;N
REVEL	Benign	0.070
Sift	Benign	0.84	T;T;T;T
Sift4G	Benign	0.19	T;T;T;T
Polyphen		0.26, 0.22	.;B;B;.
Vest4		0.21
MVP		0.19
MPC		0.013
ClinPred		0.0023	T
GERP RS		1.3
Varity_R		0.13
gMVP		0.27

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: rs111970215; hg19: chr2-102958718;