rs4986958

Positions:

• chr21-33414987-C-G
• chrNW_003315970.2-9559-C-G
• chr21-33414987-C-T
• chrNW_003315970.2-9559-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_005534.4(IFNGR2):​c.173C>G​(p.Thr58Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0131 in 1,614,056 control chromosomes in the GnomAD database, including 912 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (460 hom., cov: 32)
  • Exomes 𝑓: 0.0096 (452 hom.)
• Consequence: IFNGR2 NM_005534.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.359

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 -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=0.0018488467).
• BP6: Variant 21-33414987-C-G is Benign according to our data. Variant chr21-33414987-C-G is described in ClinVar as [Benign]. Clinvar id is 36376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.141 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFNGR2	NM_005534.4	c.173C>G	p.Thr58Arg	missense_variant	2/7	ENST00000290219.11	NP_005525.2
IFNGR2	NM_001329128.2	c.230C>G	p.Thr77Arg	missense_variant	3/8		NP_001316057.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFNGR2	ENST00000290219.11	c.173C>G	p.Thr58Arg	missense_variant	2/7	1	NM_005534.4	ENSP00000290219.5

Frequencies

GnomAD3 genomes AF: 0.0463 AC: 7039 AN: 152090 Hom.: 458 Cov.: 32

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0292

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00613

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00595

Gnomad OTH AF: 0.0425

GnomAD3 exomes AF: 0.0155 AC: 3900 AN: 251482 Hom.: 190 AF XY: 0.0124 AC XY: 1688 AN XY: 135918

Gnomad AFR exome AF: 0.147

Gnomad AMR exome AF: 0.0151

Gnomad ASJ exome AF: 0.00784

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00216

Gnomad FIN exome AF: 0.00564

Gnomad NFE exome AF: 0.00555

Gnomad OTH exome AF: 0.0138

GnomAD4 exome AF: 0.00960 AC: 14039 AN: 1461848 Hom.: 452 Cov.: 32 AF XY: 0.00883 AC XY: 6425 AN XY: 727224

Gnomad4 AFR exome AF: 0.149

Gnomad4 AMR exome AF: 0.0165

Gnomad4 ASJ exome AF: 0.00735

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00286

Gnomad4 FIN exome AF: 0.00481

Gnomad4 NFE exome AF: 0.00594

Gnomad4 OTH exome AF: 0.0150

GnomAD4 genome AF: 0.0463 AC: 7043 AN: 152208 Hom.: 460 Cov.: 32 AF XY: 0.0451 AC XY: 3360 AN XY: 74428

Gnomad4 AFR AF: 0.144

Gnomad4 AMR AF: 0.0292

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00613

Gnomad4 NFE AF: 0.00596

Gnomad4 OTH AF: 0.0421

Alfa AF: 0.00769 Hom.: 19

Bravo AF: 0.0525

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.145 AC: 637

ESP6500EA AF: 0.00593 AC: 51

ExAC AF: 0.0171 AC: 2081

Asia WGS AF: 0.00635 AC: 24 AN: 3478

EpiCase AF: 0.00578

EpiControl AF: 0.00699

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

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	GeneDx	Jun 09, 2021	- -

Immunodeficiency 28 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Interferon gamma receptor deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing;curation

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 18, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.41	T;.
Eigen	Benign	-0.074
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.083	N
LIST_S2	Benign	0.71	T;T
MetaRNN	Benign	0.0018	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.7	M;.
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Benign	0.24
Sift	Uncertain	0.019	D;D
Sift4G	Benign	0.13	T;T
Polyphen		0.88	P;P
Vest4		0.15
MPC		1.2
ClinPred		0.029	T
GERP RS		4.5
Varity_R		0.24
gMVP		0.35

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: rs4986958; hg19: chr21-34787294; COSMIC: COSV51639478;