rs17129772

Variant names:

• chr1-67320405-A-G
• rs17129772
• NM_001374259.2:c.37A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001374259.2(IL12RB2):​c.37A>G​(p.Met13Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00252 in 1,613,998 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M13I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.013 (43 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (44 hom.)
• Consequence: IL12RB2 NM_001374259.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.221
• Publications: 5 publications found

Genes affected

IL12RB2 (HGNC:5972): (interleukin 12 receptor subunit beta 2) The protein encoded by this gene is a type I transmembrane protein identified as a subunit of the interleukin 12 receptor complex. The coexpression of this and IL12RB1 proteins was shown to lead to the formation of high-affinity IL12 binding sites and reconstitution of IL12 dependent signaling. The expression of this gene is up-regulated by interferon gamma in Th1 cells, and plays a role in Th1 cell differentiation. The up-regulation of this gene is found to be associated with a number of infectious diseases, such as Crohn's disease and leprosy, which is thought to contribute to the inflammatory response and host defense. Several transcript variants encoding different isoforms and non-protein coding transcripts have been found for this gene. [provided by RefSeq, Apr 2012]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002959013).
• BP6: Variant 1-67320405-A-G is Benign according to our data. Variant chr1-67320405-A-G is described in ClinVar as Benign. ClinVar VariationId is 775560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.013 (1973/152342) while in subpopulation AFR AF = 0.0456 (1896/41568). AF 95% confidence interval is 0.0439. There are 43 homozygotes in GnomAd4. There are 942 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 43 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374259.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL12RB2	NM_001374259.2	MANE Select	c.37A>G	p.Met13Val	missense	Exon 3 of 17	NP_001361188.1	Q99665-1
	IL12RB2	NM_001559.3		c.37A>G	p.Met13Val	missense	Exon 2 of 16	NP_001550.1	Q99665-1
	IL12RB2	NM_001258215.1		c.37A>G	p.Met13Val	missense	Exon 2 of 14	NP_001245144.1	Q99665-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL12RB2	ENST00000674203.2	MANE Select	c.37A>G	p.Met13Val	missense	Exon 3 of 17	ENSP00000501329.1	Q99665-1
	IL12RB2	ENST00000262345.5	TSL:1	c.37A>G	p.Met13Val	missense	Exon 2 of 16	ENSP00000262345.1	Q99665-1
	IL12RB2	ENST00000544434.5	TSL:1	c.37A>G	p.Met13Val	missense	Exon 2 of 14	ENSP00000442443.1	Q99665-3

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1962 AN: 152224 Hom.: 42 Cov.: 32

Gnomad AFR AF: 0.0455

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00366

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00766

GnomAD2 exomes AF: 0.00357 AC: 897 AN: 251240 AF XY: 0.00244

Gnomad AFR exome AF: 0.0483

Gnomad AMR exome AF: 0.00240

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.00143 AC: 2097 AN: 1461656 Hom.: 44 Cov.: 31 AF XY: 0.00122 AC XY: 888 AN XY: 727144

African (AFR) AF: 0.0495 AC: 1656 AN: 33468

American (AMR) AF: 0.00233 AC: 104 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39628

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5762

European-Non Finnish (NFE) AF: 0.0000791 AC: 88 AN: 1111912

Other (OTH) AF: 0.00353 AC: 213 AN: 60382

GnomAD4 genome AF: 0.0130 AC: 1973 AN: 152342 Hom.: 43 Cov.: 32 AF XY: 0.0126 AC XY: 942 AN XY: 74510

African (AFR) AF: 0.0456 AC: 1896 AN: 41568

American (AMR) AF: 0.00366 AC: 56 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68036

Other (OTH) AF: 0.00758 AC: 16 AN: 2112

Alfa AF: 0.00490 Hom.: 40

Bravo AF: 0.0147

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0458 AC: 202

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00422 AC: 512

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	IL12RB2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.026
DANN	Benign	0.42
DEOGEN2	Benign	0.046	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.19	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.2	N
PhyloP100		-0.22
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.75	N
REVEL	Benign	0.028
Sift	Benign	0.71	T
Sift4G	Benign	0.64	T
Polyphen		0.0	B
Vest4		0.046
MVP		0.64
MPC		0.13
ClinPred		0.00039	T
GERP RS		-2.5
Varity_R		0.041
gMVP		0.57
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs17129772; hg19: chr1-67786088; COSMIC: COSV99057470;