Genetic Variant ENST00000433395.7:c.710-2668C>T (chr21-33265726-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.229

Publications

25 publications found

Variant links:

COSMIC-nc: COSV51615456

Genes affected

IFNAR2-IL10RB (HGNC:):

IFNAR2-IL10RB links:

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

IL10RB-DT links:

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 links:

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ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFNAR2	NM_001289125.3 link	c.*2226C>T		downstream_gene_variant		ENST00000342136.9	NP_001276054.1	P48551-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFNAR2-IL10RB	ENST00000433395.7 link	c.710-2668C>T		intron_variant	Intron 7 of 12	5		ENSP00000388223.3		H0Y3Z8
IFNAR2	ENST00000342136.9 link	c.*2226C>T		downstream_gene_variant		1	NM_001289125.3	ENSP00000343957.5		P48551-1

Frequencies

GnomAD3 genomes

AF:

0.208

AC:

31574

AN:

151594

Hom.:

3897

Cov.:

show subpopulations

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.:

AF XY:

0.264

AC XY:

18326

AN XY:

69480

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

1025

2050

3076

4101

5126

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.208

AC:

31595

AN:

151712

Hom.:

3900

Cov.:

AF XY:

0.218

AC XY:

16128

AN XY:

74136

show subpopulations

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:

AN:

294

European-Non Finnish (NFE)

AF:

0.189

AC:

12815

AN:

67922

Other (OTH)

AF:

0.209

AC:

439

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1183

2365

3548

4730

5913

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

5.0

(source)

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

Publications

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ENST00000433395.7:c.710-2668C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over