rs9808753

Variant names:

• chr21-33415005-A-G
• rs9808753
• NM_005534.4:c.191A>G

Variant summary

Our verdict is Benign. The variant received -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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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:5
• Conservation: PhyloP100: 0.175
• Publications: 118 publications found

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 Gene-Disease associations (from GenCC):

• immunodeficiency 28

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• autosomal dominant mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR2 deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive Mendelian susceptibility to mycobacterial diseases due to complete IFNgammaR2 deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive Mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR2 deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 1169473.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.408 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005534.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNGR2	NM_005534.4	MANE Select	c.191A>G	p.Gln64Arg	missense	Exon 2 of 7	NP_005525.2
	IFNGR2	NM_001329128.2		c.248A>G	p.Gln83Arg	missense	Exon 3 of 8	NP_001316057.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNGR2	ENST00000290219.11	TSL:1 MANE Select	c.191A>G	p.Gln64Arg	missense	Exon 2 of 7	ENSP00000290219.5
	IFNGR2	ENST00000381995.5	TSL:5	c.248A>G	p.Gln83Arg	missense	Exon 3 of 8	ENSP00000371425.1
	IFNGR2	ENST00000696724.1		c.86A>G	p.Gln29Arg	missense	Exon 1 of 7	ENSP00000512835.1

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

GnomAD2 exomes AF: 0.196 AC: 49315 AN: 251460 AF XY: 0.195

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 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

African (AFR) AF: 0.228 AC: 7626 AN: 33478

American (AMR) AF: 0.201 AC: 8969 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 3579 AN: 26136

East Asian (EAS) AF: 0.487 AC: 19328 AN: 39692

South Asian (SAS) AF: 0.282 AC: 24316 AN: 86252

European-Finnish (FIN) AF: 0.188 AC: 10039 AN: 53384

Middle Eastern (MID) AF: 0.117 AC: 672 AN: 5764

European-Non Finnish (NFE) AF: 0.137 AC: 151821 AN: 1111810

Other (OTH) AF: 0.173 AC: 10416 AN: 60376

GnomAD4 genome AF: 0.179 AC: 27172 AN: 152062 Hom.: 2849 Cov.: 32 AF XY: 0.182 AC XY: 13506 AN XY: 74336

African (AFR) AF: 0.225 AC: 9347 AN: 41454

American (AMR) AF: 0.158 AC: 2410 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 475 AN: 3470

East Asian (EAS) AF: 0.423 AC: 2182 AN: 5164

South Asian (SAS) AF: 0.296 AC: 1429 AN: 4826

European-Finnish (FIN) AF: 0.189 AC: 2003 AN: 10578

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.130 AC: 8866 AN: 67980

Other (OTH) AF: 0.153 AC: 323 AN: 2112

Alfa AF: 0.150 Hom.: 6240

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

Submissions by phenotype

Immunodeficiency 28 Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

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
MetaRNN	Benign	0.00051	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.33	N
PhyloP100		0.17
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.091
Sift	Benign	1.0	T
Sift4G	Benign	0.90	T
Polyphen		0.0010	B
Vest4		0.050
MPC		0.43
ClinPred		0.00030	T
GERP RS		-1.3
Varity_R		0.043
gMVP		0.43
Mutation Taster		=91/9	polymorphism (auto)

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

Other links and lift over

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