rs28938777

Variant names:

• chr2-113062148-A-G
• rs28938777
• NM_012275.3:c.140A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-113062148-A-G
• chr2-113062148-A-T
• chr2-113062148-A-C

Variant summary

Our verdict is Benign. The variant received -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. 12/21 in silico tools predict 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. N47I) 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:6
• Conservation: PhyloP100: 1.32
• Publications: 14 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Genomics England PanelApp
• pustulosis palmaris et plantaris

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 529887.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 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.140A>G	p.Asn47Ser	missense	Exon 4 of 5	NP_036407.1	Q9UBH0
	IL36RN	NM_173170.1		c.140A>G	p.Asn47Ser	missense	Exon 4 of 5	NP_775262.1	Q9UBH0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL36RN	ENST00000393200.7	TSL:1 MANE Select	c.140A>G	p.Asn47Ser	missense	Exon 4 of 5	ENSP00000376896.2	Q9UBH0
	IL36RN	ENST00000346807.7	TSL:1	c.140A>G	p.Asn47Ser	missense	Exon 4 of 5	ENSP00000259212.3	Q9UBH0
	IL36RN	ENST00000437409.2	TSL:1	c.140A>G	p.Asn47Ser	missense	Exon 3 of 4	ENSP00000409262.2	Q9UBH0

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

GnomAD2 exomes AF: 0.00479 AC: 1204 AN: 251190 AF XY: 0.00444

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 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

African (AFR) AF: 0.000597 AC: 20 AN: 33480

American (AMR) AF: 0.000201 AC: 9 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0369 AC: 1465 AN: 39700

South Asian (SAS) AF: 0.00148 AC: 128 AN: 86258

European-Finnish (FIN) AF: 0.00170 AC: 91 AN: 53416

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000258 AC: 287 AN: 1111956

Other (OTH) AF: 0.00280 AC: 169 AN: 60386

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

African (AFR) AF: 0.000963 AC: 40 AN: 41516

American (AMR) AF: 0.000392 AC: 6 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.0490 AC: 253 AN: 5166

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4818

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10612

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

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 67970

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00163 Hom.: 11

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Generalized pustular psoriasis (2)
-	-	2	not provided (2)
-	-	1	Acrodermatitis continua suppurativa of Hallopeau (1)
-	-	1	Autoinflammatory syndrome (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.3
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.28
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.018	D
Polyphen		1.0	D
Vest4		0.21
MVP		0.76
MPC		0.26
ClinPred		0.043	T
GERP RS		4.2
PromoterAI		-0.034	Neutral
Varity_R		0.10
gMVP		0.40
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

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