21-33424455-C-T

Variant names:

• chr21-33424455-C-T
• rs2012075
• NM_005534.4:c.413-2429C>T

Variant summary

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

The NM_005534.4(IFNGR2):​c.413-2429C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.878 in 152,188 control chromosomes in the GnomAD database, including 58,753 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 0.88 (58753 hom., cov: 31)
• Consequence: IFNGR2 NM_005534.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.34
• Publications: 11 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=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

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.413-2429C>T		intron	N/A	NP_005525.2
	IFNGR2	NM_001329128.2		c.470-2429C>T		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.413-2429C>T		intron	N/A	ENSP00000290219.5
	IFNGR2	ENST00000381995.5	TSL:5	c.470-2429C>T		intron	N/A	ENSP00000371425.1
	IFNGR2	ENST00000696724.1		c.308-647C>T		intron	N/A	ENSP00000512835.1

Frequencies

GnomAD3 genomes AF: 0.878 AC: 133457 AN: 152072 Hom.: 58716 Cov.: 31

Gnomad AFR AF: 0.861

Gnomad AMI AF: 0.904

Gnomad AMR AF: 0.929

Gnomad ASJ AF: 0.944

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.955

Gnomad FIN AF: 0.826

Gnomad MID AF: 0.943

Gnomad NFE AF: 0.864

Gnomad OTH AF: 0.904

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

GnomAD4 genome AF: 0.878 AC: 133547 AN: 152188 Hom.: 58753 Cov.: 31 AF XY: 0.878 AC XY: 65349 AN XY: 74404

African (AFR) AF: 0.861 AC: 35742 AN: 41514

American (AMR) AF: 0.929 AC: 14207 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.944 AC: 3279 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5167 AN: 5174

South Asian (SAS) AF: 0.955 AC: 4600 AN: 4816

European-Finnish (FIN) AF: 0.826 AC: 8752 AN: 10596

Middle Eastern (MID) AF: 0.939 AC: 276 AN: 294

European-Non Finnish (NFE) AF: 0.864 AC: 58785 AN: 68008

Other (OTH) AF: 0.906 AC: 1915 AN: 2114

Alfa AF: 0.879 Hom.: 83367

Bravo AF: 0.884

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.064
DANN	Benign	0.46
PhyloP100		-3.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2012075; hg19: chr21-34796762;