rs3181219

Variant names:

• chr5-159325131-C-T
• rs3181219
• NM_002187.3:c.88+1564G>A

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_Strong

The NM_002187.3(IL12B):c.88+1564G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0831 (AC=12,643) in the gnomAD database across 152,226 control chromosomes, including 664 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.128. 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 0.083 (664 hom., cov: 32)
• Consequence: IL12B NM_002187.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.25
• Publications: 10 publications found

Genes affected

IL12B (HGNC:5970): (interleukin 12B) This gene encodes a subunit of interleukin 12, a cytokine that acts on T and natural killer cells, and has a broad array of biological activities. Interleukin 12 is a disulfide-linked heterodimer composed of the 40 kD cytokine receptor like subunit encoded by this gene, and a 35 kD subunit encoded by IL12A. This cytokine is expressed by activated macrophages that serve as an essential inducer of Th1 cells development. This cytokine has been found to be important for sustaining a sufficient number of memory/effector Th1 cells to mediate long-term protection to an intracellular pathogen. Overexpression of this gene was observed in the central nervous system of patients with multiple sclerosis (MS), suggesting a role of this cytokine in the pathogenesis of the disease. The promoter polymorphism of this gene has been reported to be associated with the severity of atopic and non-atopic asthma in children. [provided by RefSeq, Jul 2008]

IL12B Gene-Disease associations (from GenCC):

• Mendelian susceptibility to mycobacterial diseases due to complete IL12B deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia

IL12B-AS1 (HGNC:58156): ()

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	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).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.1275 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_002187.3. 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
	IL12B NM_002187.3	MANE Select	c.88+1564G>A	intron	Intron 2 of 7	Prot: NP_002178.2

IL12B NM_002187.3

MANE Select

HGVSc / HGVSpc.88+1564G>A

Exon rankIntron 2 of 7

intron

Prot: NP_002178.2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	IL12B ENST00000231228.3	TSL:1MANE Select	c.88+1564G>A	intron	Intron 2 of 7	Prot: ENSP00000231228.2 UniProt:
	IL12B ENST00000696750.1		c.-148-4611G>A	intron	Intron 1 of 4	Prot: ENSP00000512849.1 UniProt:
	IL12B-AS1 ENST00000765006.1		n.549C>T	non_coding_transcript_exon	Exon 3 of 5	Prot:

IL12B ENST00000231228.3

TSL:1MANE Select

HGVSc / HGVSpc.88+1564G>A

Exon rankIntron 2 of 7

intron

Prot: ENSP00000231228.2UniProt: P29460

IL12B ENST00000696750.1

HGVSc / HGVSpc.-148-4611G>A

Exon rankIntron 1 of 4

intron

Prot: ENSP00000512849.1UniProt: A0A8Q3WML5

IL12B-AS1 ENST00000765006.1

HGVSc / HGVSpn.549C>T

Exon rankExon 3 of 5

non_coding_transcript_exon

Prot:

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 4 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0831	AC:12639	Hom:660	AN:152106	Cov:32
GnomAD4 genome	AF: 0.0831	AC:12643	Hom:664	AN:152226	Cov:32
TOPMed (Bravo)	AF: 0.0889	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.102	AC:5068	Hom:315	AN:49748	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.101	AC:236	Hom:17	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.0508	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.0600	AC:18	Hom:	AN:300	Cov:
GenomeAsia100K	AF: 0.0520	AC:179	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.0480	AC:346	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.193	AC:34	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0316	AC:3881	Hom:75	AN:122642	Cov:
Turkish Variome	AF: 0.129	AC:200	Hom:14	AN:1546	Cov:
UK10K	AF: 0.110	AC:829	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.0551	AC:494	Hom:26	AN:8960	Cov:

Showing 14 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	5.7
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.15
DANN	Benign	0.50
GPN-Star LLR	N/A	0.061
GPN-Star score	N/A	-0.061
Mutation Taster	N/A	100/0	polymorphism (auto)
PhyloP100	Benign	-1.2

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: rs3181219;

hg19: chr5-158752139;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar