21-33408744-G-A

Variant names:

• chr21-33408744-G-A
• rs2268241
• NM_005534.4:c.73+5128G>A

Variant summary

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

The ENST00000290219.11(IFNGR2):​c.73+5128G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 152,080 control chromosomes in the GnomAD database, including 4,463 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 0.21 (4463 hom., cov: 32)
• Consequence: IFNGR2 ENST00000290219.11 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.698
• Publications: 20 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=-1.01).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.41 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000290219.11. 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+5128G>A		intron	N/A	NP_005525.2
	IFNGR2	NM_001329128.2		c.74-2092G>A		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+5128G>A		intron	N/A	ENSP00000290219.5
	IFNGR2	ENST00000381995.5	TSL:5	c.74-2092G>A		intron	N/A	ENSP00000371425.1
	IFNGR2	ENST00000405436.5	TSL:5	c.-216-2097G>A		intron	N/A	ENSP00000385044.1

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32635 AN: 151962 Hom.: 4456 Cov.: 32

Gnomad AFR AF: 0.350

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.170

Gnomad ASJ AF: 0.144

Gnomad EAS AF: 0.425

Gnomad SAS AF: 0.299

Gnomad FIN AF: 0.191

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.131

Gnomad OTH AF: 0.177

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

GnomAD4 genome AF: 0.215 AC: 32663 AN: 152080 Hom.: 4463 Cov.: 32 AF XY: 0.216 AC XY: 16093 AN XY: 74344

African (AFR) AF: 0.350 AC: 14530 AN: 41468

American (AMR) AF: 0.170 AC: 2596 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 499 AN: 3472

East Asian (EAS) AF: 0.425 AC: 2199 AN: 5174

South Asian (SAS) AF: 0.298 AC: 1432 AN: 4812

European-Finnish (FIN) AF: 0.191 AC: 2017 AN: 10560

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.131 AC: 8892 AN: 67996

Other (OTH) AF: 0.174 AC: 368 AN: 2112

Alfa AF: 0.168 Hom.: 6968

Bravo AF: 0.222

Asia WGS AF: 0.385 AC: 1335 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.35
DANN	Benign	0.20
PhyloP100		-0.70
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: rs2268241; hg19: chr21-34781050;