rs2236757

Variant names:

• chr21-33252612-A-G
• rs2236757
• NM_001289125.3:c.541-50A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 96 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: Labcorp Genetics (formerly Invitae), Ambry Genetics

IFNAR2-IL10RB (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001289125.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNAR2	NM_001289125.3	MANE Select	c.541-50A>G		intron	N/A	NP_001276054.1	P48551-1
	IFNAR2-IL10RB	NM_001414505.1		c.541-50A>G		intron	N/A	NP_001401434.1	H0Y3Z8
	IFNAR2	NM_207585.3		c.541-50A>G		intron	N/A	NP_997468.1	P48551-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNAR2	ENST00000342136.9	TSL:1 MANE Select	c.541-50A>G		intron	N/A	ENSP00000343957.5	P48551-1
	IFNAR2-IL10RB	ENST00000433395.7	TSL:5	c.541-50A>G		intron	N/A	ENSP00000388223.3	H0Y3Z8
	IFNAR2	ENST00000382264.7	TSL:1	c.541-50A>G		intron	N/A	ENSP00000371699.3	P48551-2

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

GnomAD2 exomes AF: 0.643 AC: 140987 AN: 219242 AF XY: 0.644

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 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

African (AFR) AF: 0.791 AC: 25426 AN: 32158

American (AMR) AF: 0.546 AC: 21501 AN: 39360

Ashkenazi Jewish (ASJ) AF: 0.727 AC: 17602 AN: 24198

East Asian (EAS) AF: 0.435 AC: 17128 AN: 39352

South Asian (SAS) AF: 0.590 AC: 46780 AN: 79318

European-Finnish (FIN) AF: 0.655 AC: 34015 AN: 51964

Middle Eastern (MID) AF: 0.679 AC: 3041 AN: 4476

European-Non Finnish (NFE) AF: 0.714 AC: 782599 AN: 1095894

Other (OTH) AF: 0.682 AC: 40099 AN: 58836

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

African (AFR) AF: 0.784 AC: 32524 AN: 41484

American (AMR) AF: 0.623 AC: 9520 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.729 AC: 2531 AN: 3472

East Asian (EAS) AF: 0.423 AC: 2182 AN: 5160

South Asian (SAS) AF: 0.562 AC: 2716 AN: 4830

European-Finnish (FIN) AF: 0.636 AC: 6714 AN: 10564

Middle Eastern (MID) AF: 0.663 AC: 195 AN: 294

European-Non Finnish (NFE) AF: 0.706 AC: 48013 AN: 67980

Other (OTH) AF: 0.714 AC: 1510 AN: 2114

Alfa AF: 0.705 Hom.: 25018

Bravo AF: 0.703

Asia WGS AF: 0.527 AC: 1834 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Immunodeficiency 45 (1)
-	1	-	Mortality risk in patients with severe coronavirus disease (COVID-19) (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	5.9
DANN	Benign	0.73
PhyloP100		-0.072
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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