2-102019665-G-A

Position:

• chr2-102019665-G-A

Variant summary

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

The NM_004633.4(IL1R2):​c.541G>A​(p.Glu181Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00345 in 1,612,828 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0026 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0035 (8 hom.)
• Consequence: IL1R2 NM_004633.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.524

Genes affected

IL1R2 (HGNC:5994): (interleukin 1 receptor type 2) The protein encoded by this gene is a cytokine receptor that belongs to the interleukin 1 receptor family. This protein binds interleukin alpha (IL1A), interleukin beta (IL1B), and interleukin 1 receptor, type I(IL1R1/IL1RA), and acts as a decoy receptor that inhibits the activity of its ligands. Interleukin 4 (IL4) is reported to antagonize the activity of interleukin 1 by inducing the expression and release of this cytokine. This gene and three other genes form a cytokine receptor gene cluster on chromosome 2q12. Alternative splicing results in multiple transcript variants and protein isoforms. Alternative splicing produces both membrane-bound and soluble proteins. A soluble protein is also produced by proteolytic cleavage. [provided by RefSeq, May 2012]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030221045).
• BP6: Variant 2-102019665-G-A is Benign according to our data. Variant chr2-102019665-G-A is described in ClinVar as [Benign]. Clinvar id is 711193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL1R2	NM_004633.4	c.541G>A	p.Glu181Lys	missense_variant	5/9	ENST00000332549.8	NP_004624.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL1R2	ENST00000332549.8	c.541G>A	p.Glu181Lys	missense_variant	5/9	1	NM_004633.4	ENSP00000330959	P1
IL1R2	ENST00000393414.6	c.541G>A	p.Glu181Lys	missense_variant	5/9	1		ENSP00000377066	P1
IL1R2	ENST00000441002.1	c.541G>A	p.Glu181Lys	missense_variant	4/6	1		ENSP00000414611
IL1R2	ENST00000457817.5	c.541G>A	p.Glu181Lys	missense_variant	5/5	2		ENSP00000408415

Frequencies

GnomAD3 genomes AF: 0.00258 AC: 392 AN: 152168 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00735

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00398

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00260 AC: 651 AN: 250120 Hom.: 1 AF XY: 0.00251 AC XY: 339 AN XY: 135158

Gnomad AFR exome AF: 0.000555

Gnomad AMR exome AF: 0.000263

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000957

Gnomad FIN exome AF: 0.00740

Gnomad NFE exome AF: 0.00378

Gnomad OTH exome AF: 0.00262

GnomAD4 exome AF: 0.00354 AC: 5173 AN: 1460542 Hom.: 8 Cov.: 30 AF XY: 0.00349 AC XY: 2539 AN XY: 726518

Gnomad4 AFR exome AF: 0.000718

Gnomad4 AMR exome AF: 0.000270

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000931

Gnomad4 FIN exome AF: 0.00734

Gnomad4 NFE exome AF: 0.00407

Gnomad4 OTH exome AF: 0.00234

GnomAD4 genome AF: 0.00257 AC: 392 AN: 152286 Hom.: 4 Cov.: 33 AF XY: 0.00247 AC XY: 184 AN XY: 74464

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00735

Gnomad4 NFE AF: 0.00398

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.0120 Hom.: 821

Bravo AF: 0.00194

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00349 AC: 30

ExAC AF: 0.00247 AC: 300

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00273

EpiControl AF: 0.00338

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	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.89
DANN	Benign	0.65
DEOGEN2	Benign	0.10	T;T;T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0093	N
LIST_S2	Benign	0.68	.;T;T;T
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.0030	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.32	N;N;.;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.56	N;N;N;N
REVEL	Benign	0.051
Sift	Benign	0.83	T;T;T;T
Sift4G	Benign	0.64	T;T;T;T
Polyphen		0.0070	B;B;.;.
Vest4		0.071
MVP		0.12
MPC		0.11
ClinPred		0.0027	T
GERP RS		-8.3
Varity_R		0.12
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs28385682; hg19: chr2-102636127;