rs2236757

chr21-33252612-A-G

Variant summary

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

The NM_001289125.3(IFNAR2):c.541-50A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.694 in 1,577,648 control chromosomes in the GnomAD database, including 383,727 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (37862 hom., cov: 32)
  • Exomes 𝑓: 0.69 (345865 hom.)
• Consequence: IFNAR2 NM_001289125.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:2
• Conservation: PhyloP100: -0.0720

Genes affected

IFNAR2 (HGNC:5433): (interferon alpha and beta receptor subunit 2) The protein encoded by this gene is a type I membrane protein that forms one of the two chains of a receptor for interferons alpha and beta. Binding and activation of the receptor stimulates Janus protein kinases, which in turn phosphorylate several proteins, including STAT1 and STAT2. The protein belongs to the type II cytokine receptor family. Mutations in this gene are associated with Immunodeficiency 45. [provided by RefSeq, Jul 2020]

IFNAR2-IL10RB (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 21-33252612-A-G is Benign according to our data. Variant chr21-33252612-A-G is described in ClinVar as [Benign]. Clinvar id is 1684583.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.777 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFNAR2	NM_001289125.3	c.541-50A>G		intron_variant		ENST00000342136.9
IFNAR2-IL10RB	NM_001414505.1	c.541-50A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFNAR2	ENST00000342136.9	c.541-50A>G		intron_variant		1	NM_001289125.3	P2

Frequencies

GnomAD3 genomes AF: 0.701 AC: 106528 AN: 151974 Hom.: 37836 Cov.: 32

Gnomad AFR AF: 0.784

Gnomad AMI AF: 0.771

Gnomad AMR AF: 0.623

Gnomad ASJ AF: 0.729

Gnomad EAS AF: 0.422

Gnomad SAS AF: 0.562

Gnomad FIN AF: 0.636

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.706

Gnomad OTH AF: 0.717

GnomAD3 exomes AF: 0.643 AC: 140987 AN: 219242 Hom.: 46455 AF XY: 0.644 AC XY: 76072 AN XY: 118120

Gnomad AFR exome AF: 0.787

Gnomad AMR exome AF: 0.537

Gnomad ASJ exome AF: 0.723

Gnomad EAS exome AF: 0.419

Gnomad SAS exome AF: 0.581

Gnomad FIN exome AF: 0.646

Gnomad NFE exome AF: 0.697

Gnomad OTH exome AF: 0.673

GnomAD4 exome AF: 0.693 AC: 988191 AN: 1425556 Hom.: 345865 Cov.: 33 AF XY: 0.690 AC XY: 487679 AN XY: 706452

Gnomad4 AFR exome AF: 0.791

Gnomad4 AMR exome AF: 0.546

Gnomad4 ASJ exome AF: 0.727

Gnomad4 EAS exome AF: 0.435

Gnomad4 SAS exome AF: 0.590

Gnomad4 FIN exome AF: 0.655

Gnomad4 NFE exome AF: 0.714

Gnomad4 OTH exome AF: 0.682

GnomAD4 genome AF: 0.701 AC: 106605 AN: 152092 Hom.: 37862 Cov.: 32 AF XY: 0.690 AC XY: 51311 AN XY: 74340

Gnomad4 AFR AF: 0.784

Gnomad4 AMR AF: 0.623

Gnomad4 ASJ AF: 0.729

Gnomad4 EAS AF: 0.423

Gnomad4 SAS AF: 0.562

Gnomad4 FIN AF: 0.636

Gnomad4 NFE AF: 0.706

Gnomad4 OTH AF: 0.714

Alfa AF: 0.709 Hom.: 12186

Bravo AF: 0.703

Asia WGS AF: 0.527 AC: 1834 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mortality risk in patients with severe coronavirus disease (COVID-19) Uncertain:1

Uncertain significance, no assertion criteria provided

research

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

May 06, 2022

- -

not specified Benign:1

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 83% of patients studied by a panel of primary immunodeficiencies. Number of patients: 79. Only high quality variants are reported. -

Immunodeficiency 45 Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	5.9
Dann	Benign	0.73

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: rs2236757; hg19: chr21-34624917; COSMIC: COSV59746837; COSMIC: COSV59746837;