21-33403590-TCGCCGCCGCCGC-T

Variant names:

• chr21-33403590-TCGCCGCCGCCGC-T
• rs765468464
• NM_005534.4:c.51_62delCGCCGCCGCCGC

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM4 BS1_Supporting

The NM_005534.4(IFNGR2):​c.51_62delCGCCGCCGCCGC​(p.Ala18_Ala21del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000168 in 1,370,096 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A17A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: IFNGR2 NM_005534.4 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.20
• Publications: 2 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: Uncertain_significance. The variant received 1 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_005534.4.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000139 (17/1219792) while in subpopulation MID AF = 0.00116 (4/3450). AF 95% confidence interval is 0.000395. There are 0 homozygotes in GnomAdExome4. There are 8 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNGR2	NM_005534.4	MANE Select	c.51_62delCGCCGCCGCCGC	p.Ala18_Ala21del	disruptive_inframe_deletion	Exon 1 of 7	NP_005525.2
	IFNGR2	NM_001329128.2		c.51_62delCGCCGCCGCCGC	p.Ala18_Ala21del	disruptive_inframe_deletion	Exon 1 of 8	NP_001316057.1	E7EUY1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNGR2	ENST00000290219.11	TSL:1 MANE Select	c.51_62delCGCCGCCGCCGC	p.Ala18_Ala21del	disruptive_inframe_deletion	Exon 1 of 7	ENSP00000290219.5	P38484
	IFNGR2	ENST00000964420.1		c.51_62delCGCCGCCGCCGC	p.Ala18_Ala21del	disruptive_inframe_deletion	Exon 1 of 9	ENSP00000634479.1
	IFNGR2	ENST00000897490.1		c.51_62delCGCCGCCGCCGC	p.Ala18_Ala21del	disruptive_inframe_deletion	Exon 1 of 8	ENSP00000567549.1

Frequencies

GnomAD3 genomes AF: 0.0000399 AC: 6 AN: 150198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000139 AC: 17 AN: 1219792 Hom.: 0 AF XY: 0.0000134 AC XY: 8 AN XY: 598222

African (AFR) AF: 0.000325 AC: 8 AN: 24578

American (AMR) AF: 0.00 AC: 0 AN: 18944

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19830

East Asian (EAS) AF: 0.00 AC: 0 AN: 26094

South Asian (SAS) AF: 0.00 AC: 0 AN: 57392

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28774

Middle Eastern (MID) AF: 0.00116 AC: 4 AN: 3450

European-Non Finnish (NFE) AF: 0.00000403 AC: 4 AN: 991578

Other (OTH) AF: 0.0000203 AC: 1 AN: 49152

GnomAD4 genome AF: 0.0000399 AC: 6 AN: 150304 Hom.: 0 Cov.: 32 AF XY: 0.0000272 AC XY: 2 AN XY: 73426

African (AFR) AF: 0.000122 AC: 5 AN: 41098

American (AMR) AF: 0.00 AC: 0 AN: 15154

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5044

South Asian (SAS) AF: 0.00 AC: 0 AN: 4782

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10108

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67382

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Immunodeficiency 28 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.2
Mutation Taster		=159/41	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs765468464; hg19: chr21-34775896;