2-113059444-C-T

Variant names:

• chr2-113059444-C-T
• rs28938771
• NM_012275.3:c.6C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_012275.3(IL36RN):​c.6C>T​(p.Val2Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000366 in 1,613,854 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0021 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: IL36RN NM_012275.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.842
• Publications: 5 publications found

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]

IL36RN Gene-Disease associations (from GenCC):

• psoriasis 14, pustular

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• pustulosis palmaris et plantaris

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 2-113059444-C-T is Benign according to our data. Variant chr2-113059444-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 529889.
• BP7: Synonymous conserved (PhyloP=-0.842 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00206 (313/152160) while in subpopulation AFR AF = 0.00704 (292/41504). AF 95% confidence interval is 0.00637. There are 3 homozygotes in GnomAd4. There are 140 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012275.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL36RN	NM_012275.3	MANE Select	c.6C>T	p.Val2Val	synonymous	Exon 2 of 5	NP_036407.1
	IL36RN	NM_173170.1		c.6C>T	p.Val2Val	synonymous	Exon 2 of 5	NP_775262.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL36RN	ENST00000393200.7	TSL:1 MANE Select	c.6C>T	p.Val2Val	synonymous	Exon 2 of 5	ENSP00000376896.2
	IL36RN	ENST00000346807.7	TSL:1	c.6C>T	p.Val2Val	synonymous	Exon 2 of 5	ENSP00000259212.3
	IL36RN	ENST00000437409.2	TSL:1	c.6C>T	p.Val2Val	synonymous	Exon 1 of 4	ENSP00000409262.2

Frequencies

GnomAD3 genomes AF: 0.00203 AC: 309 AN: 152044 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00696

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000983

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000485 AC: 122 AN: 251460 AF XY: 0.000383

Gnomad AFR exome AF: 0.00708

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000190 AC: 277 AN: 1461694 Hom.: 0 Cov.: 31 AF XY: 0.000161 AC XY: 117 AN XY: 727132

African (AFR) AF: 0.00714 AC: 239 AN: 33476

American (AMR) AF: 0.000268 AC: 12 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5606

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112010

Other (OTH) AF: 0.000381 AC: 23 AN: 60376

GnomAD4 genome AF: 0.00206 AC: 313 AN: 152160 Hom.: 3 Cov.: 32 AF XY: 0.00188 AC XY: 140 AN XY: 74396

African (AFR) AF: 0.00704 AC: 292 AN: 41504

American (AMR) AF: 0.000981 AC: 15 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68016

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.000734 Hom.: 0

Bravo AF: 0.00234

Asia WGS AF: 0.000866 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Generalized pustular psoriasis (2)
-	-	1	Autoinflammatory syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	8.1
DANN	Benign	0.79
PhyloP100		-0.84
PromoterAI		0.031	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs28938771; hg19: chr2-113817021;