19-18072116-G-C

Position:

chr19-18072116-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2BP4_StrongBP6_Very_StrongBS1

The NM_005535.3(IL12RB1):c.1017C>G(p.His339Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000319 in 1,610,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

IL12RB1
NM_005535.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0110

Variant links:

Genes affected

IL12RB1 (HGNC:5971): (interleukin 12 receptor subunit beta 1) The protein encoded by this gene is a type I transmembrane protein that belongs to the hemopoietin receptor superfamily. This protein binds to interleukine 12 (IL12) with a low affinity, and is thought to be a part of IL12 receptor complex. This protein forms a disulfide-linked oligomer, which is required for its IL12 binding activity. The coexpression of this and IL12RB2 proteins was shown to lead to the formation of high-affinity IL12 binding sites and reconstitution of IL12 dependent signaling. Mutations in this gene impair the development of interleukin-17-producing T lymphocytes and result in increased susceptibility to mycobacterial and Salmonella infections. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

IL12RB1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.008882284).

BP6

Variant 19-18072116-G-C is Benign according to our data. Variant chr19-18072116-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 779643.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 = 0.00172 (262/152368) while in subpopulation AFR AF= 0.00594 (247/41596). AF 95% confidence interval is 0.00533. There are 0 homozygotes in gnomad4. There are 116 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL12RB1	NM_005535.3 linkuse as main transcript	c.1017C>G	p.His339Gln	missense_variant	9/17	ENST00000593993.7	NP_005526.1	P42701-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
IL12RB1	ENST00000593993.7 linkuse as main transcript	c.1017C>G	p.His339Gln	missense_variant	9/17	1	NM_005535.3	ENSP00000472165.2	P42701-1
IL12RB1	ENST00000600835.6 linkuse as main transcript	c.1017C>G	p.His339Gln	missense_variant	10/18	1		ENSP00000470788.1	P42701-1
IL12RB1	ENST00000322153.11 linkuse as main transcript	c.1017C>G	p.His339Gln	missense_variant	9/10	1		ENSP00000314425.5	P42701-3

Frequencies

GnomAD3 genomes

AF:

0.00171

AC:

261

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00593

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

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:

0.000478

GnomAD3 exomes

AF:

0.000446

AC:

112

AN:

250882

Hom.:

AF XY:

0.000295

AC XY:

AN XY:

135684

show subpopulations

Gnomad AFR exome

AF:

0.00628

Gnomad AMR exome

AF:

0.000232

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000173

AC:

252

AN:

1457854

Hom.:

Cov.:

AF XY:

0.000160

AC XY:

116

AN XY:

725502

show subpopulations

Gnomad4 AFR exome

AF:

0.00614

Gnomad4 AMR exome

AF:

0.000268

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000451

Gnomad4 OTH exome

AF:

0.000448

GnomAD4 genome

AF:

0.00172

AC:

262

AN:

152368

Hom.:

Cov.:

AF XY:

0.00156

AC XY:

116

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.00594

Gnomad4 AMR

AF:

0.000784

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:

0.000473

Alfa

AF:

0.000119

Hom.:

Bravo

AF:

0.00192

ESP6500AA

AF:

0.00817

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000576

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.42

CADD

Benign

7.6

DANN

Benign

0.65

DEOGEN2

Benign

0.22

T;T;.

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.059

LIST_S2

Benign

0.44

.;T;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.0089

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

M;M;M

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.8

.;.;N

REVEL

Benign

0.071

Sift4G

Benign

0.50

T;T;T

Polyphen

0.16

B;B;B

Vest4

0.13

MutPred

0.085

Gain of phosphorylation at T340 (P = 0.2398);Gain of phosphorylation at T340 (P = 0.2398);Gain of phosphorylation at T340 (P = 0.2398);

MVP

0.49

MPC

0.089

ClinPred

0.026

GERP RS

3.4

Varity_R

0.056

gMVP

0.25

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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