rs397514629

Variant names:

• chr2-113062577-C-A
• NM_012275.3:c.368C>A

Your query was ambiguous. Multiple possible variants found:

• chr2-113062577-C-A
• chr2-113062577-C-G
• chr2-113062577-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_012275.3(IL36RN):​c.368C>A​(p.Thr123Lys) 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 1,461,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. T123R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: IL36RN NM_012275.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.417

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a chain Interleukin-36 receptor antagonist protein (size 153) in uniprot entity I36RA_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_012275.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-113062577-C-G is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL36RN	NM_012275.3	c.368C>A	p.Thr123Lys	missense_variant	Exon 5 of 5	ENST00000393200.7	NP_036407.1
IL36RN	NM_173170.1	c.368C>A	p.Thr123Lys	missense_variant	Exon 5 of 5		NP_775262.1
IL36RN	XM_047443918.1	c.368C>A	p.Thr123Lys	missense_variant	Exon 6 of 6		XP_047299874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL36RN	ENST00000393200.7	c.368C>A	p.Thr123Lys	missense_variant	Exon 5 of 5	1	NM_012275.3	ENSP00000376896.2
IL36RN	ENST00000346807.7	c.368C>A	p.Thr123Lys	missense_variant	Exon 5 of 5	1		ENSP00000259212.3
IL36RN	ENST00000437409.2	c.368C>A	p.Thr123Lys	missense_variant	Exon 4 of 4	1		ENSP00000409262.2
IL36RN	ENST00000514072.1	c.56C>A	p.Thr19Lys	missense_variant	Exon 1 of 2	3		ENSP00000475308.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461618 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727138

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D;D
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.43	N
LIST_S2	Uncertain	0.87	.;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Pathogenic	3.5	M;M
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-5.0	D;D
REVEL	Uncertain	0.58
Sift	Uncertain	0.016	D;D
Sift4G	Uncertain	0.030	D;D
Polyphen		1.0	D;D
Vest4		0.78
MutPred		0.84		Gain of methylation at T123 (P = 0.0031);Gain of methylation at T123 (P = 0.0031);
MVP		0.85
MPC		0.47
ClinPred		0.98	D
GERP RS		4.2
Varity_R		0.88
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-113820154;