rs56287471

chr5-159323135-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_002187.3(IL12B):c.283G>A(p.Glu95Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00031 in 1,614,144 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E95D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (3 hom.)
• Consequence: IL12B NM_002187.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -1.97

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0053356886).
• BP6: Variant 5-159323135-C-T is Benign according to our data. Variant chr5-159323135-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 541814.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00139 (212/152306) while in subpopulation AFR AF= 0.00498 (207/41554). AF 95% confidence interval is 0.00443. There are 0 homozygotes in gnomad4. There are 86 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL12B	NM_002187.3	c.283G>A	p.Glu95Lys	missense_variant	3/8	ENST00000231228.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL12B	ENST00000231228.3	c.283G>A	p.Glu95Lys	missense_variant	3/8	1	NM_002187.3	P1
IL12B	ENST00000696750.1	c.-148-2615G>A		intron_variant
IL12B	ENST00000696751.1	c.283G>A	p.Glu95Lys	missense_variant, NMD_transcript_variant	3/7
	ENST00000521472.6	n.290-2399C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 212 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00500

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000378 AC: 95 AN: 251394 Hom.: 0 AF XY: 0.000243 AC XY: 33 AN XY: 135856

Gnomad AFR exome AF: 0.00523

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000197 AC: 288 AN: 1461838 Hom.: 3 Cov.: 33 AF XY: 0.000182 AC XY: 132 AN XY: 727222

Gnomad4 AFR exome AF: 0.00675

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.000513

GnomAD4 genome AF: 0.00139 AC: 212 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.00115 AC XY: 86 AN XY: 74480

Gnomad4 AFR AF: 0.00498

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000355 Hom.: 0

Bravo AF: 0.00181

ESP6500AA AF: 0.00567 AC: 25

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000420 AC: 51

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Mendelian susceptibility to mycobacterial diseases due to complete IL12B deficiency Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Nov 28, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	IL12B NM_002187.2 exon 3 p.Glu95Lys (c.283G>A): This variant has not been reported in the literature but is present in 0.5% (131/24968) of African alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/5-158750143-C-T?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:541841). This variant amino acid Lysine (Lys) is present in >15 species including mammals and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

IL12B-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 18, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	0.0020
Dann	Benign	0.95
DEOGEN2	Benign	0.19	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.0053	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.72	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.010
Sift	Benign	0.19	T
Sift4G	Benign	0.32	T
Polyphen		0.047	B
Vest4		0.15
MVP		0.35
MPC		0.34
ClinPred		0.0062	T
GERP RS		0.21
Varity_R		0.16
gMVP		0.64

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: rs56287471; hg19: chr5-158750143; COSMIC: COSV51454631; COSMIC: COSV51454631;