rs3213119

Positions:

• chr5-159316780-C-A

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.892G>T​(p.Val298Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0268 in 1,614,030 control chromosomes in the GnomAD database, including 649 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (40 hom., cov: 33)
  • Exomes 𝑓: 0.027 (609 hom.)
• Consequence: IL12B NM_002187.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.06

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=0.0036674142).
• BP6: Variant 5-159316780-C-A is Benign according to our data. Variant chr5-159316780-C-A is described in ClinVar as [Benign]. Clinvar id is 352572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-159316780-C-A is described in Lovd as [Benign]. Variant chr5-159316780-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0212 (3224/152302) while in subpopulation NFE AF= 0.0304 (2067/68028). AF 95% confidence interval is 0.0293. There are 40 homozygotes in gnomad4. There are 1578 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 40 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL12B	NM_002187.3	c.892G>T	p.Val298Phe	missense_variant	7/8	ENST00000231228.3	NP_002178.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL12B	ENST00000231228.3	c.892G>T	p.Val298Phe	missense_variant	7/8	1	NM_002187.3	ENSP00000231228	P1
IL12B	ENST00000696750.1	c.262G>T	p.Val88Phe	missense_variant	4/5			ENSP00000512849
IL12B	ENST00000696751.1	c.*387G>T		3_prime_UTR_variant, NMD_transcript_variant	6/7			ENSP00000512850
	ENST00000521472.6	n.289+5366C>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0212 AC: 3224 AN: 152184 Hom.: 40 Cov.: 33

Gnomad AFR AF: 0.00610

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0289

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0291

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0304

Gnomad OTH AF: 0.0244

GnomAD3 exomes AF: 0.0207 AC: 5150 AN: 248422 Hom.: 81 AF XY: 0.0203 AC XY: 2721 AN XY: 134366

Gnomad AFR exome AF: 0.00527

Gnomad AMR exome AF: 0.0209

Gnomad ASJ exome AF: 0.0152

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00242

Gnomad FIN exome AF: 0.0303

Gnomad NFE exome AF: 0.0300

Gnomad OTH exome AF: 0.0207

GnomAD4 exome AF: 0.0273 AC: 39960 AN: 1461728 Hom.: 609 Cov.: 32 AF XY: 0.0263 AC XY: 19159 AN XY: 727160

Gnomad4 AFR exome AF: 0.00508

Gnomad4 AMR exome AF: 0.0217

Gnomad4 ASJ exome AF: 0.0164

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00254

Gnomad4 FIN exome AF: 0.0290

Gnomad4 NFE exome AF: 0.0316

Gnomad4 OTH exome AF: 0.0236

GnomAD4 genome AF: 0.0212 AC: 3224 AN: 152302 Hom.: 40 Cov.: 33 AF XY: 0.0212 AC XY: 1578 AN XY: 74470

Gnomad4 AFR AF: 0.00609

Gnomad4 AMR AF: 0.0288

Gnomad4 ASJ AF: 0.0159

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.0291

Gnomad4 NFE AF: 0.0304

Gnomad4 OTH AF: 0.0241

Alfa AF: 0.0286 Hom.: 162

Bravo AF: 0.0210

TwinsUK AF: 0.0289 AC: 107

ALSPAC AF: 0.0298 AC: 115

ESP6500AA AF: 0.00567 AC: 25

ESP6500EA AF: 0.0303 AC: 261

ExAC AF: 0.0205 AC: 2485

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0286

EpiControl AF: 0.0313

ClinVar

Significance: Benign

Submissions summary: Benign:2

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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Pathogenic	3.2	M
MutationTaster	Benign	0.56	D
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.13
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.98	D
Vest4		0.24
MPC		0.90
ClinPred		0.066	T
GERP RS		5.7
Varity_R		0.64
gMVP		0.69

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

Publications

LitVar

Other links and lift over

dbSNP: rs3213119; hg19: chr5-158743788;