Genetic Variant NM_001374259.2:c.75A>G (chr1-67320443-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001374259.2(IL12RB2):c.75A>G(p.Ile25Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

IL12RB2
NM_001374259.2 missense, splice_region

Scores

Splicing: ADA: 0.6455

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0300

Publications

0 publications found

Variant links:

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]

IL12RB2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.26207626).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IL12RB2	NM_001374259.2	MANE Select	c.75A>G	p.Ile25Met	missense splice_region	Exon 3 of 17	NP_001361188.1	Q99665-1
IL12RB2	NM_001559.3		c.75A>G	p.Ile25Met	missense splice_region	Exon 2 of 16	NP_001550.1	Q99665-1
IL12RB2	NM_001258215.1		c.75A>G	p.Ile25Met	missense splice_region	Exon 2 of 14	NP_001245144.1	Q99665-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IL12RB2	ENST00000674203.2	MANE Select	c.75A>G	p.Ile25Met	missense splice_region	Exon 3 of 17	ENSP00000501329.1	Q99665-1
IL12RB2	ENST00000262345.5	TSL:1	c.75A>G	p.Ile25Met	missense splice_region	Exon 2 of 16	ENSP00000262345.1	Q99665-1
IL12RB2	ENST00000544434.5	TSL:1	c.75A>G	p.Ile25Met	missense splice_region	Exon 2 of 14	ENSP00000442443.1	Q99665-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

Eigen

Uncertain

0.19

Eigen_PC

Benign

0.17

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.81

M_CAP

Benign

0.0062

MetaRNN

Benign

0.26

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

PhyloP100

0.030

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.3

REVEL

Benign

0.19

Sift

Benign

0.032

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.22

MutPred

0.62

Gain of ubiquitination at K22 (P = 0.0767)

MVP

0.57

MPC

0.23

ClinPred

0.61

GERP RS

2.7

Varity_R

0.10

gMVP

0.43

Mutation Taster

=74/26

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.65

dbscSNV1_RF

Benign

0.58

SpliceAI score (max)

0.12

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over