Genetic Variant NM_012275.3:c.4G>A (chr2-113059442-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_012275.3(IL36RN):c.4G>A(p.Val2Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

IL36RN
NM_012275.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.75

Publications

0 publications found

Variant links:

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

IL36RN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.35611582).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL36RN	NM_012275.3 link	c.4G>A	p.Val2Ile	missense_variant	Exon 2 of 5	ENST00000393200.7	NP_036407.1	Q9UBH0A0A024R518
IL36RN	NM_173170.1 link	c.4G>A	p.Val2Ile	missense_variant	Exon 2 of 5		NP_775262.1	Q9UBH0A0A024R518
IL36RN	XM_047443918.1 link	c.4G>A	p.Val2Ile	missense_variant	Exon 3 of 6		XP_047299874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IL36RN	ENST00000393200.7 link	c.4G>A	p.Val2Ile	missense_variant	Exon 2 of 5	1	NM_012275.3	ENSP00000376896.2	Q9UBH0
IL36RN	ENST00000346807.7 link	c.4G>A	p.Val2Ile	missense_variant	Exon 2 of 5	1		ENSP00000259212.3	Q9UBH0
IL36RN	ENST00000437409.2 link	c.4G>A	p.Val2Ile	missense_variant	Exon 1 of 4	1		ENSP00000409262.2	Q9UBH0C9JTH1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461694

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727136

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000178

AC:

AN:

5608

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112004

Other (OTH)

AF:

0.00

AC:

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.082

T;T;.

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.66

.;T;T

M_CAP

Benign

0.0060

MetaRNN

Benign

0.36

T;T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.4

L;L;.

PhyloP100

2.8

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.27

N;N;N

REVEL

Benign

0.068

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.98

D;D;.

Vest4

0.38

MutPred

0.28

Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);

MVP

0.64

MPC

0.46

ClinPred

0.96

GERP RS

4.6

PromoterAI

0.072

Neutral

(source)

Varity_R

0.13

gMVP

0.14

Mutation Taster

=83/17

polymorphism

(source)

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

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NM_012275.3:c.4G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over