rs999788

Variant names:

• chr21-33265726-C-T
• rs999788
• ENST00000433395.7:c.710-2668C>T

Variant summary

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

The ENST00000433395.7(IFNAR2-IL10RB):​c.710-2668C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 273,880 control chromosomes in the GnomAD database, including 8,393 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 0.21 (3900 hom., cov: 31)
  • Exomes 𝑓: 0.25 (4493 hom.)
• Consequence: IFNAR2-IL10RB ENST00000433395.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.229
• Publications: 25 publications found

Genes affected

IFNAR2-IL10RB (HGNC:):

IL10RB-DT (HGNC:44303): (IL10RB divergent transcript)

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)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.539 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000433395.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL10RB-DT	NR_038974.1		n.375G>A		non_coding_transcript_exon	Exon 2 of 2
	IFNAR2-IL10RB	NM_001414505.1		c.710-2668C>T		intron	N/A	NP_001401434.1
	IFNAR2	NM_001289125.3	MANE Select	c.*2226C>T		downstream_gene	N/A	NP_001276054.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNAR2-IL10RB	ENST00000433395.7	TSL:5	c.710-2668C>T		intron	N/A	ENSP00000388223.3
	IL10RB-DT	ENST00000411998.4	TSL:2	n.416G>A		non_coding_transcript_exon	Exon 2 of 2
	IFNAR2-IL10RB	ENST00000432231.1	TSL:2	n.308-10870C>T		intron	N/A	ENSP00000413946.1

Frequencies

GnomAD3 genomes AF: 0.208 AC: 31574 AN: 151594 Hom.: 3897 Cov.: 31

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.283

Gnomad ASJ AF: 0.229

Gnomad EAS AF: 0.556

Gnomad SAS AF: 0.370

Gnomad FIN AF: 0.259

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.189

Gnomad OTH AF: 0.206

GnomAD4 exome AF: 0.246 AC: 30029 AN: 122168 Hom.: 4493 Cov.: 0 AF XY: 0.264 AC XY: 18326 AN XY: 69480

African (AFR) AF: 0.128 AC: 192 AN: 1500

American (AMR) AF: 0.339 AC: 1587 AN: 4676

Ashkenazi Jewish (ASJ) AF: 0.220 AC: 481 AN: 2188

East Asian (EAS) AF: 0.562 AC: 1278 AN: 2274

South Asian (SAS) AF: 0.355 AC: 10916 AN: 30776

European-Finnish (FIN) AF: 0.238 AC: 1487 AN: 6242

Middle Eastern (MID) AF: 0.268 AC: 250 AN: 932

European-Non Finnish (NFE) AF: 0.184 AC: 12472 AN: 67812

Other (OTH) AF: 0.237 AC: 1366 AN: 5768

GnomAD4 genome AF: 0.208 AC: 31595 AN: 151712 Hom.: 3900 Cov.: 31 AF XY: 0.218 AC XY: 16128 AN XY: 74136

African (AFR) AF: 0.137 AC: 5669 AN: 41350

American (AMR) AF: 0.284 AC: 4326 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.229 AC: 793 AN: 3460

East Asian (EAS) AF: 0.556 AC: 2854 AN: 5134

South Asian (SAS) AF: 0.370 AC: 1769 AN: 4780

European-Finnish (FIN) AF: 0.259 AC: 2724 AN: 10500

Middle Eastern (MID) AF: 0.259 AC: 76 AN: 294

European-Non Finnish (NFE) AF: 0.189 AC: 12815 AN: 67922

Other (OTH) AF: 0.209 AC: 439 AN: 2102

Alfa AF: 0.196 Hom.: 700

Bravo AF: 0.209

Asia WGS AF: 0.442 AC: 1534 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.0
DANN	Benign	0.67
PhyloP100		0.23

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: rs999788; hg19: chr21-34638031; COSMIC: COSV51615456;