21-33403590-TCGCCGCCGCCGC-TCGCCGCCGC

Variant names:

• chr21-33403590-TCGC-T
• rs765468464
• NM_005534.4:c.60_62delCGC

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PM4_Supporting BP6

The NM_005534.4(IFNGR2):​c.60_62delCGC​(p.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 0.000703 in 1,211,410 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00070 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: IFNGR2 NM_005534.4 disruptive_inframe_deletion
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.411
• 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 0 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_005534.4. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 21-33403590-TCGC-T is Benign according to our data. Variant chr21-33403590-TCGC-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3350397.Status of the report is no_assertion_criteria_provided, 0 stars.

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.60_62delCGC	p.Ala21del	disruptive_inframe_deletion	Exon 1 of 7	NP_005525.2
	IFNGR2	NM_001329128.2		c.60_62delCGC	p.Ala21del	disruptive_inframe_deletion	Exon 1 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.60_62delCGC	p.Ala21del	disruptive_inframe_deletion	Exon 1 of 7	ENSP00000290219.5
	IFNGR2	ENST00000381995.5	TSL:5	c.60_62delCGC	p.Ala21del	disruptive_inframe_deletion	Exon 1 of 8	ENSP00000371425.1
	IFNGR2	ENST00000439213.5	TSL:5	n.60_62delCGC		non_coding_transcript_exon	Exon 1 of 7	ENSP00000407541.1

Frequencies

GnomAD3 genomes AF: 0.00000666 AC: 1 AN: 150188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000661

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00347 AC: 175 AN: 50422 AF XY: 0.00313

Gnomad AFR exome AF: 0.00836

Gnomad AMR exome AF: 0.00304

Gnomad ASJ exome AF: 0.00272

Gnomad EAS exome AF: 0.00552

Gnomad FIN exome AF: 0.00327

Gnomad NFE exome AF: 0.00375

Gnomad OTH exome AF: 0.00314

GnomAD4 exome AF: 0.000703 AC: 852 AN: 1211410 Hom.: 0 AF XY: 0.000812 AC XY: 482 AN XY: 593408

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

African (AFR) AF: 0.000737 AC: 18 AN: 24414

American (AMR) AF: 0.00200 AC: 37 AN: 18460

Ashkenazi Jewish (ASJ) AF: 0.00143 AC: 28 AN: 19636

East Asian (EAS) AF: 0.000309 AC: 8 AN: 25918

South Asian (SAS) AF: 0.00340 AC: 190 AN: 55814

European-Finnish (FIN) AF: 0.00183 AC: 52 AN: 28404

Middle Eastern (MID) AF: 0.000583 AC: 2 AN: 3432

European-Non Finnish (NFE) AF: 0.000477 AC: 471 AN: 986504

Other (OTH) AF: 0.000942 AC: 46 AN: 48828

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000666 AC: 1 AN: 150188 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73310

⚠️ 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: 40980

American (AMR) AF: 0.0000661 AC: 1 AN: 15130

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5060

South Asian (SAS) AF: 0.00 AC: 0 AN: 4786

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10106

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67390

Other (OTH) AF: 0.00 AC: 0 AN: 2068

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

IFNGR2-related disorder Benign:1

Jul 15, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.41
Mutation Taster		=88/12	polymorphism

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: rs765468464; hg19: chr21-34775896; COSMIC: COSV107327072;