1-67320405-A-G

Position:

chr1-67320405-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.221

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 775560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-67320405-A-G is described in Lovd as [Benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 43 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL12RB2	NM_001374259.2 linkuse as main transcript	c.37A>G	p.Met13Val	missense_variant	3/17	ENST00000674203.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL12RB2	ENST00000674203.2 linkuse as main transcript	c.37A>G	p.Met13Val	missense_variant	3/17		NM_001374259.2	P1	Q99665-1

Frequencies

GnomAD3 genomes

AF:

0.0129

AC:

1962

AN:

152224

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.00357

AC:

897

AN:

251240

Hom.:

AF XY:

0.00244

AC XY:

332

AN XY:

135788

show subpopulations

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 SAS exome

AF:

0.000294

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.:

Cov.:

AF XY:

0.00122

AC XY:

888

AN XY:

727144

show subpopulations

Gnomad4 AFR exome

AF:

0.0495

Gnomad4 AMR exome

AF:

0.00233

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000791

Gnomad4 OTH exome

AF:

0.00353

GnomAD4 genome

AF:

0.0130

AC:

1973

AN:

152342

Hom.:

Cov.:

AF XY:

0.0126

AC XY:

942

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.0456

Gnomad4 AMR

AF:

0.00366

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00758

Alfa

AF:

0.00263

Hom.:

Bravo

AF:

0.0147

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0458

AC:

202

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00422

AC:

512

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

IL12RB2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 02, 2019

This variant is classified as 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

0.063

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.026

DANN

Benign

0.42

DEOGEN2

Benign

0.046

T;.;.;.;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.19

.;T;T;T;T

MetaRNN

Benign

0.0030

T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-1.2

N;N;.;N;N

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

0.75

N;N;N;N;.

REVEL

Benign

0.028

Sift

Benign

0.71

T;T;T;T;.

Sift4G

Benign

0.64

T;T;T;T;.

Polyphen

0.0

B;.;.;B;B

Vest4

0.046

MVP

0.64

MPC

0.13

ClinPred

0.00039

GERP RS

-2.5

Varity_R

0.041

gMVP

0.57

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over