NM_001562.4:c.398G>C

Variant names:

• chr11-112143780-C-G
• rs1364344013
• NM_001562.4:c.398G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001562.4(IL18):​c.398G>C​(p.Ser133Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 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. S133N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: IL18 NM_001562.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.320
• Publications: 0 publications found

Genes affected

IL18 (HGNC:5986): (interleukin 18) The protein encoded by this gene is a proinflammatory cytokine of the IL-1 family that is constitutively found as a precursor within the cytoplasm of a variety of cells including macrophages and keratinocytes. The inactive IL-18 precursor is processed to its active form by caspase-1, and is capable of stimulating interferon gamma production, and of regulating both T helper (Th) 1 and Th2 responses. This cytokine has been implicated in the injury of different organs, and in potentially fatal conditions characterized by a cytokine storm. In humans, IL-18 gene is located on chromosome 11. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Aug 2020]

ENSG00000255292 (HGNC:):

ACMG classification

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=0.30021805).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001562.4. 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
	IL18	NM_001562.4	MANE Select	c.398G>C	p.Ser133Thr	missense	Exon 6 of 6	NP_001553.1	Q14116-1
	IL18	NM_001386420.1		c.398G>C	p.Ser133Thr	missense	Exon 6 of 6	NP_001373349.1	Q14116-1
	IL18	NM_001243211.2		c.386G>C	p.Ser129Thr	missense	Exon 5 of 5	NP_001230140.1	Q14116-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL18	ENST00000280357.12	TSL:1 MANE Select	c.398G>C	p.Ser133Thr	missense	Exon 6 of 6	ENSP00000280357.7	Q14116-1
	IL18	ENST00000524595.6	TSL:1	c.386G>C	p.Ser129Thr	missense	Exon 5 of 5	ENSP00000434561.1	Q14116-2
	IL18	ENST00000525547.5	TSL:1	n.1174G>C		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T
Eigen	Benign	0.040
Eigen_PC	Benign	-0.0083
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.32
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.072
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.053	T
Polyphen		0.84	P
Vest4		0.16
MutPred		0.62		Loss of disorder (P = 0.0681)
MVP		0.54
MPC		0.88
ClinPred		0.93	D
GERP RS		3.1
Varity_R		0.54
gMVP		0.31
Mutation Taster		=87/13	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: rs1364344013; hg19: chr11-112014503;