21-33241950-T-G

Position:

chr21-33241950-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000342136.9(IFNAR2):c.28T>G(p.Phe10Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.335 in 1,606,830 control chromosomes in the GnomAD database, including 95,222 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F10I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.32 ( 8284 hom., cov: 32)

Exomes 𝑓: 0.34 ( 86938 hom. )

Consequence

IFNAR2
ENST00000342136.9 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4O:1

Conservation

PhyloP100: -1.92

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 links:

IFNAR2-IL10RB (HGNC:):

IFNAR2-IL10RB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=3.302767E-5).

BP6

Variant 21-33241950-T-G is Benign according to our data. Variant chr21-33241950-T-G is described in ClinVar as [Benign]. Clinvar id is 1170800.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.562 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFNAR2	NM_001289125.3 linkuse as main transcript	c.28T>G	p.Phe10Val	missense_variant	2/9	ENST00000342136.9	NP_001276054.1
IFNAR2-IL10RB	NM_001414505.1 linkuse as main transcript	c.28T>G	p.Phe10Val	missense_variant	2/13		NP_001401434.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFNAR2	ENST00000342136.9 linkuse as main transcript	c.28T>G	p.Phe10Val	missense_variant	2/9	1	NM_001289125.3	ENSP00000343957	P2	P48551-1

Frequencies

GnomAD3 genomes

AF:

0.317

AC:

48202

AN:

151950

Hom.:

8274

Cov.:

show subpopulations

Gnomad AFR

AF:

0.198

Gnomad AMI

AF:

0.245

Gnomad AMR

AF:

0.399

Gnomad ASJ

AF:

0.319

Gnomad EAS

AF:

0.581

Gnomad SAS

AF:

0.492

Gnomad FIN

AF:

0.404

Gnomad MID

AF:

0.380

Gnomad NFE

AF:

0.326

Gnomad OTH

AF:

0.311

GnomAD3 exomes

AF:

0.383

AC:

95264

AN:

248934

Hom.:

19832

AF XY:

0.386

AC XY:

51937

AN XY:

134618

show subpopulations

Gnomad AFR exome

AF:

0.190

Gnomad AMR exome

AF:

0.474

Gnomad ASJ exome

AF:

0.322

Gnomad EAS exome

AF:

0.582

Gnomad SAS exome

AF:

0.475

Gnomad FIN exome

AF:

0.391

Gnomad NFE exome

AF:

0.331

Gnomad OTH exome

AF:

0.354

GnomAD4 exome

AF:

0.337

AC:

490087

AN:

1454762

Hom.:

86938

Cov.:

AF XY:

0.341

AC XY:

247021

AN XY:

723956

show subpopulations

Gnomad4 AFR exome

AF:

0.191

Gnomad4 AMR exome

AF:

0.467

Gnomad4 ASJ exome

AF:

0.321

Gnomad4 EAS exome

AF:

0.565

Gnomad4 SAS exome

AF:

0.470

Gnomad4 FIN exome

AF:

0.385

Gnomad4 NFE exome

AF:

0.315

Gnomad4 OTH exome

AF:

0.349

GnomAD4 genome

AF:

0.317

AC:

48244

AN:

152068

Hom.:

8284

Cov.:

AF XY:

0.329

AC XY:

24420

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.198

Gnomad4 AMR

AF:

0.400

Gnomad4 ASJ

AF:

0.319

Gnomad4 EAS

AF:

0.580

Gnomad4 SAS

AF:

0.492

Gnomad4 FIN

AF:

0.404

Gnomad4 NFE

AF:

0.326

Gnomad4 OTH

AF:

0.315

Alfa

AF:

0.322

Hom.:

12293

Bravo

AF:

0.311

TwinsUK

AF:

0.315

AC:

1168

ALSPAC

AF:

0.299

AC:

1151

ESP6500AA

AF:

0.188

AC:

828

ESP6500EA

AF:

0.317

AC:

2726

ExAC

AF:

0.378

AC:

45947

Asia WGS

AF:

0.519

AC:

1801

AN:

3478

EpiCase

AF:

0.333

EpiControl

AF:

0.337

ClinVar

Significance: Benign

Submissions summary: Benign:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 69% of patients studied by a panel of primary immunodeficiencies. Number of patients: 66. Only high quality variants are reported. -

Immunodeficiency 45

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Mortality risk in patients with severe coronavirus disease (COVID-19)

Other:1

association, no assertion criteria provided

research

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

May 06, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.045

BayesDel_addAF

Benign

-0.84

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.0080

DANN

Benign

0.56

DEOGEN2

Benign

0.10

.;.;T;.;T

Eigen

Benign

-2.2

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.0024

LIST_S2

Benign

0.15

.;T;.;T;T

MetaRNN

Benign

0.000033

T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-1.3

N;N;N;N;.

MutationTaster

Benign

1.0

P;P;P;P;P;P

PrimateAI

Benign

0.26

PROVEAN

Benign

1.6

N;N;N;N;N

REVEL

Benign

0.0050

Sift

Benign

0.77

T;T;T;T;T

Sift4G

Benign

0.62

T;T;T;T;T

Polyphen

0.0

B;B;B;B;.

Vest4

0.046

MPC

0.046

ClinPred

0.0044

GERP RS

-7.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.052

gMVP

0.35

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over