2-113062148-A-G

Variant summary

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

The NM_012275.3(IL36RN):c.140A>G(p.Asn47Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00156 in 1,613,984 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N47D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0023 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (33 hom.)
• Consequence: IL36RN NM_012275.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.32

Genes affected

IL36RN (HGNC:15561): (interleukin 36 receptor antagonist) The protein encoded by this gene is a member of the interleukin 1 cytokine family. This cytokine was shown to specifically inhibit the activation of NF-kappaB induced by interleukin 1 family, member 6 (IL1F6). This gene and eight other interleukin 1 family genes form a cytokine gene cluster on chromosome 2. Two alternatively spliced transcript variants encoding the same protein have been reported. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0048855245).
• BP6: Variant 2-113062148-A-G is Benign according to our data. Variant chr2-113062148-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 529887.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-113062148-A-G is described in Lovd as [Likely_benign]. Variant chr2-113062148-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00228 (347/152164) while in subpopulation EAS AF= 0.049 (253/5166). AF 95% confidence interval is 0.044. There are 12 homozygotes in gnomad4. There are 208 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL36RN	NM_012275.3	c.140A>G	p.Asn47Ser	missense_variant	4/5	ENST00000393200.7
IL36RN	NM_173170.1	c.140A>G	p.Asn47Ser	missense_variant	4/5
IL36RN	XM_047443918.1	c.140A>G	p.Asn47Ser	missense_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL36RN	ENST00000393200.7	c.140A>G	p.Asn47Ser	missense_variant	4/5	1	NM_012275.3	P1
IL36RN	ENST00000346807.7	c.140A>G	p.Asn47Ser	missense_variant	4/5	1		P1
IL36RN	ENST00000437409.2	c.140A>G	p.Asn47Ser	missense_variant	3/4	1		P1

Frequencies

GnomAD3 genomes AF: 0.00230 AC: 350 AN: 152046 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0493

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00479 AC: 1204 AN: 251190 Hom.: 25 AF XY: 0.00444 AC XY: 603 AN XY: 135766

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0561

Gnomad SAS exome AF: 0.00140

Gnomad FIN exome AF: 0.00171

Gnomad NFE exome AF: 0.000484

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00148 AC: 2170 AN: 1461820 Hom.: 33 Cov.: 32 AF XY: 0.00147 AC XY: 1066 AN XY: 727212

Gnomad4 AFR exome AF: 0.000597

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0369

Gnomad4 SAS exome AF: 0.00148

Gnomad4 FIN exome AF: 0.00170

Gnomad4 NFE exome AF: 0.000258

Gnomad4 OTH exome AF: 0.00280

GnomAD4 genome AF: 0.00228 AC: 347 AN: 152164 Hom.: 12 Cov.: 32 AF XY: 0.00280 AC XY: 208 AN XY: 74400

Gnomad4 AFR AF: 0.000963

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0490

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00193 Hom.: 10

Bravo AF: 0.00241

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00460 AC: 558

Asia WGS AF: 0.0260 AC: 89 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Generalized pustular psoriasis Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Acrodermatitis continua suppurativa of Hallopeau Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 12, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 23, 2019

This variant is associated with the following publications: (PMID: 26589685, 33560533, 32613680, 31180159, 27542682) -

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 23, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	17
Dann	Uncertain	0.98
DEOGEN2	Benign	0.16	T;T;.
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.80	D
MetaRNN	Benign	0.0049	T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.1	M;M;.
MutationTaster	Benign	0.98	N;N
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.4	N;N;N
REVEL	Benign	0.28
Sift	Uncertain	0.027	D;D;D
Sift4G	Uncertain	0.018	D;D;T
Polyphen		1.0	D;D;.
Vest4		0.21
MVP		0.76
MPC		0.26
ClinPred		0.043	T
GERP RS		4.2
Varity_R		0.10
gMVP		0.40

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: rs28938777; hg19: chr2-113819725; COSMIC: COSV61011096; COSMIC: COSV61011096;