Genetic Variant IFNAR2:p.Ala285Ser (chr21-33262573-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000382264.7(IFNAR2):c.853G>T(p.Ala285Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000882 in 566,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A285T) has been classified as Benign.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0000088 ( 0 hom. )

Consequence

IFNAR2
ENST00000382264.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.773

Publications

31 publications found

Variant links:

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 links:

IFNAR2-IL10RB (HGNC:):

IFNAR2-IL10RB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.054858863).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFNAR2	NM_001289125.3 link	c.841-220G>T		intron_variant	Intron 8 of 8	ENST00000342136.9	NP_001276054.1	P48551-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFNAR2	ENST00000342136.9 link	c.841-220G>T		intron_variant	Intron 8 of 8	1	NM_001289125.3	ENSP00000343957.5		P48551-1
IFNAR2-IL10RB	ENST00000433395.7 link	c.710-5821G>T		intron_variant	Intron 7 of 12	5		ENSP00000388223.3		H0Y3Z8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000141

AC:

AN:

141474

AF XY:

0.0000259

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000149

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000882

AC:

AN:

566620

Hom.:

Cov.:

AF XY:

0.00000979

AC XY:

AN XY:

306476

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

15992

American (AMR)

AF:

0.00

AC:

AN:

34562

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20166

East Asian (EAS)

AF:

0.00

AC:

AN:

32162

South Asian (SAS)

AF:

0.00

AC:

AN:

63576

European-Finnish (FIN)

AF:

0.0000281

AC:

AN:

35596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2908

European-Non Finnish (NFE)

AF:

0.0000121

AC:

AN:

330738

Other (OTH)

AF:

0.00

AC:

AN:

30920

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000470

Hom.:

897

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.73

CADD

Benign

3.5

(source)

DANN

Benign

0.80

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.37

.;T

M_CAP

Benign

0.0021

MetaRNN

Benign

0.055

T;T

MetaSVM

Benign

-1.0

PhyloP100

0.77

PROVEAN

Benign

0.43

N;N

REVEL

Benign

0.026

Sift

Benign

0.73

T;T

Sift4G

Benign

0.54

T;T

Polyphen

0.25

B;B

Vest4

0.13

MutPred

0.49

Gain of sheet (P = 0.0125);Gain of sheet (P = 0.0125);

MVP

0.16

ClinPred

0.041

GERP RS

0.56

Mutation Taster

=98/2

polymorphism

(source)

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over