chr21-33403590-TCGCCGC-T

Variant names:

• chr21-33403590-TCGCCGC-T
• rs765468464
• NM_005534.4:c.57_62delCGCCGC

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_005534.4(IFNGR2):​c.57_62delCGCCGC​(p.Ala20_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 0.00000803 in 1,370,082 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000066 (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 2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_005534.4.

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.57_62delCGCCGC	p.Ala20_Ala21del	disruptive_inframe_deletion	Exon 1 of 7	NP_005525.2
	IFNGR2	NM_001329128.2		c.57_62delCGCCGC	p.Ala20_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.57_62delCGCCGC	p.Ala20_Ala21del	disruptive_inframe_deletion	Exon 1 of 7	ENSP00000290219.5	P38484
	IFNGR2	ENST00000964420.1		c.57_62delCGCCGC	p.Ala20_Ala21del	disruptive_inframe_deletion	Exon 1 of 9	ENSP00000634479.1
	IFNGR2	ENST00000897490.1		c.57_62delCGCCGC	p.Ala20_Ala21del	disruptive_inframe_deletion	Exon 1 of 8	ENSP00000567549.1

Frequencies

GnomAD3 genomes AF: 0.0000200 AC: 3 AN: 150198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000593

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000656 AC: 8 AN: 1219778 Hom.: 0 AF XY: 0.00000669 AC XY: 4 AN XY: 598212

African (AFR) AF: 0.00 AC: 0 AN: 24578

American (AMR) AF: 0.00 AC: 0 AN: 18942

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

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

South Asian (SAS) AF: 0.0000174 AC: 1 AN: 57388

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3450

European-Non Finnish (NFE) AF: 0.00000202 AC: 2 AN: 991572

Other (OTH) AF: 0.000102 AC: 5 AN: 49150

GnomAD4 genome AF: 0.0000200 AC: 3 AN: 150304 Hom.: 0 Cov.: 32 AF XY: 0.0000272 AC XY: 2 AN XY: 73426

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 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: 0.000595 AC: 3 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: 0.00 AC: 0 AN: 67382

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000102688), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

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		=189/11	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;