rs3213096

Positions:

• chr5-159323321-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002187.3(IL12B):​c.97G>A​(p.Val33Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00532 in 1,613,866 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0054 (55 hom.)
• Consequence: IL12B NM_002187.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.58

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0053630173).
• BP6: Variant 5-159323321-C-T is Benign according to our data. Variant chr5-159323321-C-T is described in ClinVar as [Benign]. Clinvar id is 474973.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00465 (708/152330) while in subpopulation SAS AF= 0.00994 (48/4828). AF 95% confidence interval is 0.0077. There are 4 homozygotes in gnomad4. There are 376 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL12B	NM_002187.3	c.97G>A	p.Val33Ile	missense_variant	3/8	ENST00000231228.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL12B	ENST00000231228.3	c.97G>A	p.Val33Ile	missense_variant	3/8	1	NM_002187.3	P1
IL12B	ENST00000696750.1	c.-148-2801G>A		intron_variant
IL12B	ENST00000696751.1	c.97G>A	p.Val33Ile	missense_variant, NMD_transcript_variant	3/7
	ENST00000521472.6	n.290-2213C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00465 AC: 708 AN: 152212 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00596

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0101

Gnomad FIN AF: 0.0119

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00520

Gnomad OTH AF: 0.00910

GnomAD3 exomes AF: 0.00633 AC: 1589 AN: 250946 Hom.: 20 AF XY: 0.00707 AC XY: 959 AN XY: 135620

Gnomad AFR exome AF: 0.000862

Gnomad AMR exome AF: 0.00339

Gnomad ASJ exome AF: 0.00943

Gnomad EAS exome AF: 0.000598

Gnomad SAS exome AF: 0.0146

Gnomad FIN exome AF: 0.00920

Gnomad NFE exome AF: 0.00586

Gnomad OTH exome AF: 0.00701

GnomAD4 exome AF: 0.00539 AC: 7875 AN: 1461536 Hom.: 55 Cov.: 33 AF XY: 0.00565 AC XY: 4111 AN XY: 727078

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.00369

Gnomad4 ASJ exome AF: 0.00895

Gnomad4 EAS exome AF: 0.000353

Gnomad4 SAS exome AF: 0.0136

Gnomad4 FIN exome AF: 0.00834

Gnomad4 NFE exome AF: 0.00475

Gnomad4 OTH exome AF: 0.00692

GnomAD4 genome AF: 0.00465 AC: 708 AN: 152330 Hom.: 4 Cov.: 32 AF XY: 0.00505 AC XY: 376 AN XY: 74484

Gnomad4 AFR AF: 0.000914

Gnomad4 AMR AF: 0.00595

Gnomad4 ASJ AF: 0.00691

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.00994

Gnomad4 FIN AF: 0.0119

Gnomad4 NFE AF: 0.00522

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.00577 Hom.: 6

Bravo AF: 0.00413

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00570 AC: 49

ExAC AF: 0.00648 AC: 787

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.00840

EpiControl AF: 0.00777

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mendelian susceptibility to mycobacterial diseases due to complete IL12B deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2024

IL12B: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.14
Sift	Benign	0.15	T
Sift4G	Benign	0.17	T
Polyphen		0.0020	B
Vest4		0.13
MVP		0.33
MPC		0.25
ClinPred		0.0063	T
GERP RS		5.2
Varity_R		0.11
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs3213096; hg19: chr5-158750329;