21-33432659-T-C

Variant names:

• chr21-33432659-T-C
• rs1532
• NM_005534.4:c.722-55T>C

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.722-55T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.73 in 1,579,122 control chromosomes in the GnomAD database, including 424,203 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.77 (45996 hom., cov: 31)
  • Exomes 𝑓: 0.73 (378207 hom.)
• Consequence: IFNGR2 NM_005534.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.43

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 21-33432659-T-C is Benign according to our data. Variant chr21-33432659-T-C is described in ClinVar as [Benign]. Clinvar id is 1268638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.961 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFNGR2	NM_005534.4	c.722-55T>C		intron_variant	Intron 5 of 6	ENST00000290219.11	NP_005525.2
TMEM50B	XM_011529746.3	c.*2374A>G		3_prime_UTR_variant	Exon 10 of 10		XP_011528048.1
IFNGR2	NM_001329128.2	c.779-55T>C		intron_variant	Intron 6 of 7		NP_001316057.1
TMEM50B	NR_040016.2	n.2919A>G		non_coding_transcript_exon_variant	Exon 9 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFNGR2	ENST00000290219.11	c.722-55T>C		intron_variant	Intron 5 of 6	1	NM_005534.4	ENSP00000290219.5

Frequencies

GnomAD3 genomes AF: 0.773 AC: 117515 AN: 152032 Hom.: 45937 Cov.: 31

Gnomad AFR AF: 0.865

Gnomad AMI AF: 0.636

Gnomad AMR AF: 0.813

Gnomad ASJ AF: 0.644

Gnomad EAS AF: 0.984

Gnomad SAS AF: 0.776

Gnomad FIN AF: 0.794

Gnomad MID AF: 0.687

Gnomad NFE AF: 0.698

Gnomad OTH AF: 0.743

GnomAD4 exome AF: 0.725 AC: 1034793 AN: 1426972 Hom.: 378207 Cov.: 25 AF XY: 0.724 AC XY: 515612 AN XY: 712186

Gnomad4 AFR exome AF: 0.870

Gnomad4 AMR exome AF: 0.852

Gnomad4 ASJ exome AF: 0.645

Gnomad4 EAS exome AF: 0.976

Gnomad4 SAS exome AF: 0.765

Gnomad4 FIN exome AF: 0.788

Gnomad4 NFE exome AF: 0.702

Gnomad4 OTH exome AF: 0.736

GnomAD4 genome AF: 0.773 AC: 117631 AN: 152150 Hom.: 45996 Cov.: 31 AF XY: 0.780 AC XY: 58008 AN XY: 74372

Gnomad4 AFR AF: 0.866

Gnomad4 AMR AF: 0.814

Gnomad4 ASJ AF: 0.644

Gnomad4 EAS AF: 0.984

Gnomad4 SAS AF: 0.776

Gnomad4 FIN AF: 0.794

Gnomad4 NFE AF: 0.698

Gnomad4 OTH AF: 0.744

Alfa AF: 0.720 Hom.: 17672

Bravo AF: 0.781

Asia WGS AF: 0.890 AC: 3096 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.37
DANN	Benign	0.36
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1532; hg19: chr21-34804966;