21-33427043-C-T

Variant names:

• chr21-33427043-C-T
• rs11910627
• NM_005534.4:c.561+11C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005534.4(IFNGR2):​c.561+11C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,130 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 29)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: IFNGR2 NM_005534.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0310
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFNGR2	NM_005534.4	c.561+11C>T		intron_variant	Intron 4 of 6	ENST00000290219.11	NP_005525.2
IFNGR2	NM_001329128.2	c.618+11C>T		intron_variant	Intron 5 of 7		NP_001316057.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFNGR2	ENST00000290219.11	c.561+11C>T		intron_variant	Intron 4 of 6	1	NM_005534.4	ENSP00000290219.5

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457130 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725270

African (AFR) AF: 0.00 AC: 0 AN: 33326

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107834

Other (OTH) AF: 0.00 AC: 0 AN: 60218

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.80
DANN	Benign	0.73
PhyloP100		-0.031

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: rs11910627; hg19: chr21-34799350;