21-33404389-A-G

Variant names:

• chr21-33404389-A-G
• rs2284553
• NM_005534.4:c.73+773A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005534.4(IFNGR2):​c.73+773A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.683 in 152,132 control chromosomes in the GnomAD database, including 36,839 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.68 (36839 hom., cov: 32)
• Consequence: IFNGR2 NM_005534.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.05
• Publications: 73 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.886 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.73+773A>G		intron	N/A	NP_005525.2
	IFNGR2	NM_001329128.2		c.73+773A>G		intron	N/A	NP_001316057.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNGR2	ENST00000290219.11	TSL:1 MANE Select	c.73+773A>G		intron	N/A	ENSP00000290219.5
	IFNGR2	ENST00000381995.5	TSL:5	c.73+773A>G		intron	N/A	ENSP00000371425.1
	IFNGR2	ENST00000405436.5	TSL:5	c.-217+773A>G		intron	N/A	ENSP00000385044.1

Frequencies

GnomAD3 genomes AF: 0.683 AC: 103867 AN: 152010 Hom.: 36791 Cov.: 32

Gnomad AFR AF: 0.893

Gnomad AMI AF: 0.520

Gnomad AMR AF: 0.606

Gnomad ASJ AF: 0.624

Gnomad EAS AF: 0.599

Gnomad SAS AF: 0.661

Gnomad FIN AF: 0.627

Gnomad MID AF: 0.541

Gnomad NFE AF: 0.596

Gnomad OTH AF: 0.673

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.683 AC: 103971 AN: 152132 Hom.: 36839 Cov.: 32 AF XY: 0.682 AC XY: 50701 AN XY: 74352

African (AFR) AF: 0.893 AC: 37099 AN: 41528

American (AMR) AF: 0.606 AC: 9268 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.624 AC: 2168 AN: 3472

East Asian (EAS) AF: 0.600 AC: 3099 AN: 5166

South Asian (SAS) AF: 0.660 AC: 3182 AN: 4824

European-Finnish (FIN) AF: 0.627 AC: 6624 AN: 10564

Middle Eastern (MID) AF: 0.544 AC: 160 AN: 294

European-Non Finnish (NFE) AF: 0.596 AC: 40488 AN: 67970

Other (OTH) AF: 0.669 AC: 1412 AN: 2112

Alfa AF: 0.630 Hom.: 65957

Bravo AF: 0.691

Asia WGS AF: 0.684 AC: 2375 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.5
DANN	Benign	0.77
PhyloP100		-1.1
Mutation Taster		=100/0	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: rs2284553; hg19: chr21-34776695;