11-112164265-C-A

Variant names:

• chr11-112164265-C-A
• rs187238
• ENST00000532699.1:n.315-6154C>A

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-2 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -2 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_Strong

The NM_001562.4(IL18):c.-368G>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000658 (AC=1) in the gnomAD database across 152,054 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000147. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: IL18 NM_001562.4 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.22
• Publications: 541 publications found

Genes affected

ENSG00000255292 (HGNC:):

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]

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000147 — very rare for unknown gene (threshold 0.001) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001562.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	IL18 NM_001562.4	MANE Select	c.-368G>T	upstream_gene	N/A	Prot: NP_001553.1 UniProt:
	IL18 NM_001386420.1		c.-389G>T	upstream_gene	N/A	Prot: NP_001373349.1 UniProt:
	IL18 NM_001243211.2		c.-368G>T	upstream_gene	N/A	Prot: NP_001230140.1 UniProt:

IL18 NM_001562.4

MANE Select

HGVSc / HGVSpc.-368G>T

Exon rankN/A

upstream_gene

Prot: NP_001553.1UniProt: Q14116-1

IL18 NM_001386420.1

HGVSc / HGVSpc.-389G>T

Exon rankN/A

upstream_gene

Prot: NP_001373349.1UniProt: Q14116-1

IL18 NM_001243211.2

HGVSc / HGVSpc.-368G>T

Exon rankN/A

upstream_gene

Prot: NP_001230140.1UniProt: Q14116-2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ENSG00000255292 ENST00000532699.1	TSL:3	n.315-6154C>A	intron	Intron 3 of 5	Prot: ENSP00000456434.1 UniProt:
	ENSG00000255292 ENST00000525987.5	TSL:4	n.320-6154C>A	intron	Intron 3 of 5	Prot:
	ENSG00000255292 ENST00000531744.5	TSL:2	n.315-6154C>A	intron	Intron 3 of 5	Prot: ENSP00000456957.1 UniProt:

ENSG00000255292 ENST00000532699.1

TSL:3

HGVSc / HGVSpn.315-6154C>A

Exon rankIntron 3 of 5

intron

Prot: ENSP00000456434.1UniProt: H3BRW5

ENSG00000255292 ENST00000525987.5

TSL:4

HGVSc / HGVSpn.320-6154C>A

Exon rankIntron 3 of 5

intron

Prot:

ENSG00000255292 ENST00000531744.5

TSL:2

HGVSc / HGVSpn.315-6154C>A

Exon rankIntron 3 of 5

intron

Prot: ENSP00000456957.1UniProt: H3BRW5

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00000658	AC:1	Hom:0	AN:152054	Cov:32
GnomAD4 exome Warning	AF: 0.00	AC:0	Hom:0	AN:16	Cov:
GnomAD4 genome	AF: 0.00000658	AC:1	Hom:0	AN:152054	Cov:32
TOPMed (Bravo) Warning	AF: 0.00000378	AC:1	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:347	AN:18154	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.00000800	AC:1	Hom:0	AN:122780	Cov:

Showing 6 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	0.058
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.57
DANN	Benign	0.83
GPN-Star LLR	N/A	0.068
GPN-Star score	N/A	-0.068
PhyloP100	Benign	-4.2
PromoterAI	N/A	0.020	Neutral

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs187238;

hg19: chr11-112034988;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar