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). Synonymous variant affecting the same amino acid position (i.e. A20A) has been classified as Likely benign.

• 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

Sel.	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	E7EUY1

Ensembl Transcripts

Sel.	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	P38484
	IFNGR2	ENST00000964420.1		c.60_62delCGC	p.Ala21del	disruptive_inframe_deletion	Exon 1 of 9	ENSP00000634479.1
	IFNGR2	ENST00000897490.1		c.60_62delCGC	p.Ala21del	disruptive_inframe_deletion	Exon 1 of 8	ENSP00000567549.1

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

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	IFNGR2-related disorder (1)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs765468464;

hg19: chr21-34775896;

COSMIC: COSV107327072;