rs9808753

chr21-33415005-A-GchrNW_003315970.2-9576-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.175

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• 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	UniProt
IFNGR2	NM_005534.4	c.191A>G	p.Gln64Arg	missense_variant	2/7	ENST00000290219.11
IFNGR2	NM_001329128.2	c.248A>G	p.Gln83Arg	missense_variant	3/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFNGR2	ENST00000290219.11	c.191A>G	p.Gln64Arg	missense_variant	2/7	1	NM_005534.4	P1

Frequencies

GnomAD3 genomes AF: 0.179 AC: 27172 AN: 151944 Hom.: 2855 Cov.: 32

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

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.: 34 AF XY: 0.164 AC XY: 119584 AN XY: 727134

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.: 32 AF XY: 0.182 AC XY: 13506 AN XY: 74336

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Immunodeficiency 28 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2021

This variant is associated with the following publications: (PMID: 20952689, 25854761) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.67	T
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	N
LIST_S2	Benign	0.30	T;T
MetaRNN	Benign	0.00051	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.33	N;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.21	T
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	T
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

Other links and lift over

dbSNP: rs9808753; hg19: chr21-34787312; COSMIC: COSV51639508;