chr1-67321605-C-T

Position:

• chr1-67321605-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001374259.2(IL12RB2):​c.80C>T​(p.Ala27Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000766 in 1,436,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A27A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000077 (0 hom.)
• Consequence: IL12RB2 NM_001374259.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0340

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07916817).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL12RB2	NM_001374259.2	c.80C>T	p.Ala27Val	missense_variant	4/17	ENST00000674203.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL12RB2	ENST00000674203.2	c.80C>T	p.Ala27Val	missense_variant	4/17		NM_001374259.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000319 AC: 8 AN: 250972 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135700

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000766 AC: 11 AN: 1436592 Hom.: 0 Cov.: 27 AF XY: 0.0000126 AC XY: 9 AN XY: 716360

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000275

Gnomad4 OTH exome AF: 0.0000336

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 17, 2023

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 27 of the IL12RB2 protein (p.Ala27Val). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 1918323). This variant has not been reported in the literature in individuals affected with IL12RB2-related conditions. This variant is present in population databases (rs746456201, gnomAD 0.02%). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.47
DANN	Benign	0.26
DEOGEN2	Benign	0.050	T;.;.;.;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0049	N
LIST_S2	Benign	0.66	.;T;T;T;T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.079	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.2	N;N;.;N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.64	N;N;N;N;.
REVEL	Benign	0.15
Sift	Benign	1.0	T;T;T;T;.
Sift4G	Benign	1.0	T;T;T;T;.
Polyphen		0.0	B;.;.;B;B
Vest4		0.025
MutPred		0.54		Loss of catalytic residue at A27 (P = 0.0231);Loss of catalytic residue at A27 (P = 0.0231);Loss of catalytic residue at A27 (P = 0.0231);Loss of catalytic residue at A27 (P = 0.0231);Loss of catalytic residue at A27 (P = 0.0231);
MVP		0.53
MPC		0.13
ClinPred		0.011	T
GERP RS		1.8
Varity_R		0.020
gMVP		0.54

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: rs746456201; hg19: chr1-67787288; COSMIC: COSV52022463;