21-33254349-C-A

Variant names:

• chr21-33254349-C-A
• rs2834166
• NM_001289125.3:c.709+1519C>A

Variant summary

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

The NM_001289125.3(IFNAR2):​c.709+1519C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.299 in 152,010 control chromosomes in the GnomAD database, including 7,362 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 0.30 (7362 hom., cov: 32)
• Consequence: IFNAR2 NM_001289125.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.637
• 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=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.344 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFNAR2	NM_001289125.3	c.709+1519C>A		intron_variant	Intron 7 of 8	ENST00000342136.9	NP_001276054.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFNAR2	ENST00000342136.9	c.709+1519C>A		intron_variant	Intron 7 of 8	1	NM_001289125.3	ENSP00000343957.5
IFNAR2-IL10RB	ENST00000433395.7	c.709+1519C>A		intron_variant	Intron 7 of 12	5		ENSP00000388223.3

Frequencies

GnomAD3 genomes AF: 0.299 AC: 45426 AN: 151892 Hom.: 7355 Cov.: 32

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.562

Gnomad AMR AF: 0.323

Gnomad ASJ AF: 0.369

Gnomad EAS AF: 0.319

Gnomad SAS AF: 0.266

Gnomad FIN AF: 0.410

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.348

Gnomad OTH AF: 0.325

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

GnomAD4 genome AF: 0.299 AC: 45449 AN: 152010 Hom.: 7362 Cov.: 32 AF XY: 0.300 AC XY: 22269 AN XY: 74276

African (AFR) AF: 0.170 AC: 7044 AN: 41486

American (AMR) AF: 0.323 AC: 4934 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.369 AC: 1281 AN: 3472

East Asian (EAS) AF: 0.320 AC: 1656 AN: 5170

South Asian (SAS) AF: 0.266 AC: 1281 AN: 4814

European-Finnish (FIN) AF: 0.410 AC: 4314 AN: 10532

Middle Eastern (MID) AF: 0.333 AC: 98 AN: 294

European-Non Finnish (NFE) AF: 0.348 AC: 23647 AN: 67946

Other (OTH) AF: 0.324 AC: 684 AN: 2112

Alfa AF: 0.309 Hom.: 1535

Bravo AF: 0.289

Asia WGS AF: 0.276 AC: 961 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.79
DANN	Benign	0.68
PhyloP100		-0.64
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: rs2834166; hg19: chr21-34626654;