rs9808753

Positions:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_005534.4(IFNGR2):c.191A>G(p.Gln64Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.164 in 1,613,674 control chromosomes in the GnomAD database, including 25,826 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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.

Frequency

Genomes: 𝑓 0.18 ( 2849 hom., cov: 32)

Exomes 𝑓: 0.16 ( 22977 hom. )

Consequence

IFNGR2
NM_005534.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.175

Variant links:

Genes affected

IFNGR2 (HGNC:5440): (interferon gamma receptor 2) This gene (IFNGR2) encodes the non-ligand-binding beta chain of the gamma interferon receptor. Human interferon-gamma receptor is a heterodimer of IFNGR1 and IFNGR2. Defects in IFNGR2 are a cause of mendelian susceptibility to mycobacterial disease (MSMD), also known as familial disseminated atypical mycobacterial infection. MSMD is a genetically heterogeneous disease with autosomal recessive, autosomal dominant or X-linked inheritance. [provided by RefSeq, Jul 2008]

IFNGR2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a topological_domain Extracellular (size 219) in uniprot entity INGR2_HUMAN there are 10 pathogenic changes around while only 3 benign (77%) in NM_005534.4

BP4

Computational evidence support a benign effect (MetaRNN=5.0866604E-4).

BP6

Variant 21-33415005-A-G is Benign according to our data. Variant chr21-33415005-A-G is described in ClinVar as [Benign]. Clinvar id is 1169473.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-33415005-A-G is described in Lovd as [Likely_benign]. Variant chr21-33415005-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.408 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFNGR2	NM_005534.4 linkuse as main transcript	c.191A>G	p.Gln64Arg	missense_variant	2/7	ENST00000290219.11	NP_005525.2
IFNGR2	NM_001329128.2 linkuse as main transcript	c.248A>G	p.Gln83Arg	missense_variant	3/8		NP_001316057.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFNGR2	ENST00000290219.11 linkuse as main transcript	c.191A>G	p.Gln64Arg	missense_variant	2/7	1	NM_005534.4	ENSP00000290219.5		P38484

Frequencies

GnomAD3 genomes

AF:

0.179

AC:

27172

AN:

151944

Hom.:

2855

Cov.:

show subpopulations

Gnomad AFR

AF:

0.226

Gnomad AMI

AF:

0.106

Gnomad AMR

AF:

0.158

Gnomad ASJ

AF:

0.137

Gnomad EAS

AF:

0.423

Gnomad SAS

AF:

0.297

Gnomad FIN

AF:

0.189

Gnomad MID

AF:

0.123

Gnomad NFE

AF:

0.130

Gnomad OTH

AF:

0.156

GnomAD3 exomes

AF:

0.196

AC:

49315

AN:

251460

Hom.:

5990

AF XY:

0.195

AC XY:

26440

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.235

Gnomad AMR exome

AF:

0.210

Gnomad ASJ exome

AF:

0.136

Gnomad EAS exome

AF:

0.433

Gnomad SAS exome

AF:

0.286

Gnomad FIN exome

AF:

0.194

Gnomad NFE exome

AF:

0.131

Gnomad OTH exome

AF:

0.167

GnomAD4 exome

AF:

0.162

AC:

236766

AN:

1461612

Hom.:

22977

Cov.:

AF XY:

0.164

AC XY:

119584

AN XY:

727134

show subpopulations

Gnomad4 AFR exome

AF:

0.228

Gnomad4 AMR exome

AF:

0.201

Gnomad4 ASJ exome

AF:

0.137

Gnomad4 EAS exome

AF:

0.487

Gnomad4 SAS exome

AF:

0.282

Gnomad4 FIN exome

AF:

0.188

Gnomad4 NFE exome

AF:

0.137

Gnomad4 OTH exome

AF:

0.173

GnomAD4 genome

AF:

0.179

AC:

27172

AN:

152062

Hom.:

2849

Cov.:

AF XY:

0.182

AC XY:

13506

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.225

Gnomad4 AMR

AF:

0.158

Gnomad4 ASJ

AF:

0.137

Gnomad4 EAS

AF:

0.423

Gnomad4 SAS

AF:

0.296

Gnomad4 FIN

AF:

0.189

Gnomad4 NFE

AF:

0.130

Gnomad4 OTH

AF:

0.153

Alfa

AF:

0.146

Hom.:

4108

Bravo

AF:

0.181

TwinsUK

AF:

0.151

AC:

559

ALSPAC

AF:

0.138

AC:

531

ESP6500AA

AF:

0.225

AC:

991

ESP6500EA

AF:

0.138

AC:

1183

ExAC

AF:

0.196

AC:

23834

Asia WGS

AF:

0.376

AC:

1302

AN:

3478

EpiCase

AF:

0.127

EpiControl

AF:

0.123

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Immunodeficiency 28

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	This variant is associated with the following publications: (PMID: 20952689, 25854761) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 25% of patients studied by a panel of primary immunodeficiencies. Number of patients: 22. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.60

CADD

Benign

5.7

DANN

Benign

0.099

DEOGEN2

Benign

0.11

T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.30

T;T

MetaRNN

Benign

0.00051

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.33

N;.

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.010

N;N

REVEL

Benign

0.091

Sift

Benign

1.0

T;T

Sift4G

Benign

0.90

T;T

Polyphen

0.0010

B;B

Vest4

0.050

MPC

0.43

ClinPred

0.00030

GERP RS

-1.3

Varity_R

0.043

gMVP

0.43

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