chr21-33248496-A-G

Variant names:

• chr21-33248496-A-G
• rs2073362
• NM_001289125.3:c.395-213A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001289125.3(IFNAR2):​c.395-213A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0745 in 152,312 control chromosomes in the GnomAD database, including 594 homozygotes. 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: 𝑓 0.075 (594 hom., cov: 31)
• Consequence: IFNAR2 NM_001289125.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.732
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• immunodeficiency 45

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

IFNAR2-IL10RB (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFNAR2	NM_001289125.3	c.395-213A>G		intron_variant	Intron 5 of 8	ENST00000342136.9	NP_001276054.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFNAR2	ENST00000342136.9	c.395-213A>G		intron_variant	Intron 5 of 8	1	NM_001289125.3	ENSP00000343957.5
IFNAR2-IL10RB	ENST00000433395.7	c.395-213A>G		intron_variant	Intron 5 of 12	5		ENSP00000388223.3

Frequencies

GnomAD3 genomes AF: 0.0745 AC: 11345 AN: 152194 Hom.: 592 Cov.: 31

Gnomad AFR AF: 0.0166

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.0778

Gnomad EAS AF: 0.198

Gnomad SAS AF: 0.135

Gnomad FIN AF: 0.0932

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.0821

Gnomad OTH AF: 0.0690

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0745 AC: 11349 AN: 152312 Hom.: 594 Cov.: 31 AF XY: 0.0802 AC XY: 5975 AN XY: 74472

African (AFR) AF: 0.0166 AC: 690 AN: 41578

American (AMR) AF: 0.124 AC: 1903 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0778 AC: 270 AN: 3472

East Asian (EAS) AF: 0.197 AC: 1023 AN: 5192

South Asian (SAS) AF: 0.135 AC: 651 AN: 4820

European-Finnish (FIN) AF: 0.0932 AC: 989 AN: 10610

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.0821 AC: 5584 AN: 68014

Other (OTH) AF: 0.0739 AC: 156 AN: 2110

Alfa AF: 0.0802 Hom.: 977

Bravo AF: 0.0737

Asia WGS AF: 0.152 AC: 528 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.7
DANN	Benign	0.63
PhyloP100		0.73
Mutation Taster		=100/0	polymorphism (auto)

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: rs2073362; hg19: chr21-34620801;