rs11910627

chr21-33427043-C-GchrNW_003315970.2-21614-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005534.4(IFNGR2):c.561+11C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.729 in 1,605,584 control chromosomes in the GnomAD database, including 430,378 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.77 (45896 hom., cov: 29)
  • Exomes 𝑓: 0.72 (384482 hom.)
• Consequence: IFNGR2 NM_005534.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0310

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 21-33427043-C-G is Benign according to our data. Variant chr21-33427043-C-G is described in ClinVar as [Benign]. Clinvar id is 402963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-33427043-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.962 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFNGR2	NM_005534.4	c.561+11C>G		intron_variant		ENST00000290219.11
IFNGR2	NM_001329128.2	c.618+11C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFNGR2	ENST00000290219.11	c.561+11C>G		intron_variant		1	NM_005534.4	P1

Frequencies

GnomAD3 genomes AF: 0.773 AC: 117281 AN: 151802 Hom.: 45835 Cov.: 29

Gnomad AFR AF: 0.864

Gnomad AMI AF: 0.626

Gnomad AMR AF: 0.813

Gnomad ASJ AF: 0.645

Gnomad EAS AF: 0.985

Gnomad SAS AF: 0.775

Gnomad FIN AF: 0.798

Gnomad MID AF: 0.690

Gnomad NFE AF: 0.697

Gnomad OTH AF: 0.743

GnomAD3 exomes AF: 0.769 AC: 192779 AN: 250840 Hom.: 75344 AF XY: 0.760 AC XY: 103104 AN XY: 135596

Gnomad AFR exome AF: 0.871

Gnomad AMR exome AF: 0.859

Gnomad ASJ exome AF: 0.641

Gnomad EAS exome AF: 0.994

Gnomad SAS exome AF: 0.767

Gnomad FIN exome AF: 0.800

Gnomad NFE exome AF: 0.698

Gnomad OTH exome AF: 0.730

GnomAD4 exome AF: 0.724 AC: 1052300 AN: 1453664 Hom.: 384482 Cov.: 32 AF XY: 0.723 AC XY: 523217 AN XY: 723656

Gnomad4 AFR exome AF: 0.868

Gnomad4 AMR exome AF: 0.852

Gnomad4 ASJ exome AF: 0.644

Gnomad4 EAS exome AF: 0.978

Gnomad4 SAS exome AF: 0.764

Gnomad4 FIN exome AF: 0.790

Gnomad4 NFE exome AF: 0.700

Gnomad4 OTH exome AF: 0.735

GnomAD4 genome AF: 0.773 AC: 117400 AN: 151920 Hom.: 45896 Cov.: 29 AF XY: 0.780 AC XY: 57878 AN XY: 74228

Gnomad4 AFR AF: 0.864

Gnomad4 AMR AF: 0.814

Gnomad4 ASJ AF: 0.645

Gnomad4 EAS AF: 0.985

Gnomad4 SAS AF: 0.774

Gnomad4 FIN AF: 0.798

Gnomad4 NFE AF: 0.697

Gnomad4 OTH AF: 0.744

Alfa AF: 0.724 Hom.: 7369

Bravo AF: 0.781

Asia WGS AF: 0.890 AC: 3097 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 92% of patients studied by a panel of primary immunodeficiencies. Number of patients: 81. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Immunodeficiency 28 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.65
Dann	Benign	0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs11910627; hg19: chr21-34799350;