21-33432748-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 2P and 17B. PM2 BP4_Strong BP6_Very_Strong BP7 BS1

The NM_005534.4(IFNGR2):c.756C>T(p.Ser252=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000237 in 1,614,102 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00024 (1 hom.)
• Consequence: IFNGR2 NM_005534.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -4.46

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]

TMEM50B (HGNC:1280): (transmembrane protein 50B) Predicted to be involved in late endosome to vacuole transport via multivesicular body sorting pathway. Located in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 21-33432748-C-T is Benign according to our data. Variant chr21-33432748-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 717050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.46 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000223 (34/152242) while in subpopulation SAS AF= 0.000622 (3/4826). AF 95% confidence interval is 0.00023. There are 0 homozygotes in gnomad4. There are 19 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFNGR2	NM_005534.4	c.756C>T	p.Ser252=	synonymous_variant	6/7	ENST00000290219.11
IFNGR2	NM_001329128.2	c.813C>T	p.Ser271=	synonymous_variant	7/8
TMEM50B	XM_011529746.3	c.*2285G>A		3_prime_UTR_variant	10/10
TMEM50B	NR_040016.2	n.2830G>A		non_coding_transcript_exon_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFNGR2	ENST00000290219.11	c.756C>T	p.Ser252=	synonymous_variant	6/7	1	NM_005534.4	P1

Frequencies

GnomAD3 genomes AF: 0.000224 AC: 34 AN: 152124 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000259 AC: 65 AN: 251344 Hom.: 0 AF XY: 0.000331 AC XY: 45 AN XY: 135840

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.000686

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000239 AC: 349 AN: 1461860 Hom.: 1 Cov.: 35 AF XY: 0.000267 AC XY: 194 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.000638

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.000235

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152242 Hom.: 0 Cov.: 31 AF XY: 0.000255 AC XY: 19 AN XY: 74428

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000326 Hom.: 0

Bravo AF: 0.000174

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

IFNGR2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 09, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Immunodeficiency 28 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Oct 16, 2023

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2023

IFNGR2: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
Cadd	Benign	1.3
Dann	Benign	0.87
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs186369364; hg19: chr21-34805055;