21-33241945-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001289125.3(IFNAR2):c.23T>C(p.Phe8Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0834 in 1,608,462 control chromosomes in the GnomAD database, including 6,307 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.092 (699 hom., cov: 32)
  • Exomes 𝑓: 0.083 (5608 hom.)
• Consequence: IFNAR2 NM_001289125.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:3 O:1
• Conservation: PhyloP100: -1.30

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-IL10RB (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001052022).
• BP6: Variant 21-33241945-T-C is Benign according to our data. Variant chr21-33241945-T-C is described in ClinVar as [Benign]. Clinvar id is 7288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.162 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFNAR2	NM_001289125.3	c.23T>C	p.Phe8Ser	missense_variant	2/9	ENST00000342136.9
IFNAR2-IL10RB	NM_001414505.1	c.23T>C	p.Phe8Ser	missense_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFNAR2	ENST00000342136.9	c.23T>C	p.Phe8Ser	missense_variant	2/9	1	NM_001289125.3	P2

Frequencies

GnomAD3 genomes AF: 0.0917 AC: 13949 AN: 152094 Hom.: 694 Cov.: 32

Gnomad AFR AF: 0.0805

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.131

Gnomad ASJ AF: 0.0776

Gnomad EAS AF: 0.172

Gnomad SAS AF: 0.133

Gnomad FIN AF: 0.0932

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.0816

Gnomad OTH AF: 0.0841

GnomAD3 exomes AF: 0.103 AC: 25757 AN: 249278 Hom.: 1509 AF XY: 0.102 AC XY: 13711 AN XY: 134802

Gnomad AFR exome AF: 0.0774

Gnomad AMR exome AF: 0.154

Gnomad ASJ exome AF: 0.0774

Gnomad EAS exome AF: 0.176

Gnomad SAS exome AF: 0.125

Gnomad FIN exome AF: 0.0855

Gnomad NFE exome AF: 0.0808

Gnomad OTH exome AF: 0.0909

GnomAD4 exome AF: 0.0825 AC: 120178 AN: 1456250 Hom.: 5608 Cov.: 29 AF XY: 0.0842 AC XY: 61009 AN XY: 724626

Gnomad4 AFR exome AF: 0.0794

Gnomad4 AMR exome AF: 0.152

Gnomad4 ASJ exome AF: 0.0775

Gnomad4 EAS exome AF: 0.146

Gnomad4 SAS exome AF: 0.124

Gnomad4 FIN exome AF: 0.0833

Gnomad4 NFE exome AF: 0.0737

Gnomad4 OTH exome AF: 0.0926

GnomAD4 genome AF: 0.0917 AC: 13963 AN: 152212 Hom.: 699 Cov.: 32 AF XY: 0.0971 AC XY: 7227 AN XY: 74422

Gnomad4 AFR AF: 0.0805

Gnomad4 AMR AF: 0.131

Gnomad4 ASJ AF: 0.0776

Gnomad4 EAS AF: 0.172

Gnomad4 SAS AF: 0.133

Gnomad4 FIN AF: 0.0932

Gnomad4 NFE AF: 0.0816

Gnomad4 OTH AF: 0.0894

Alfa AF: 0.0867 Hom.: 1120

Bravo AF: 0.0936

TwinsUK AF: 0.0777 AC: 288

ALSPAC AF: 0.0664 AC: 256

ESP6500AA AF: 0.0756 AC: 333

ESP6500EA AF: 0.0779 AC: 670

ExAC AF: 0.105 AC: 12794

Asia WGS AF: 0.147 AC: 510 AN: 3478

EpiCase AF: 0.0834

EpiControl AF: 0.0849

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mortality risk in patients with severe coronavirus disease (COVID-19) Uncertain:1

Uncertain significance, no assertion criteria provided

research

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

May 06, 2022

- -

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 29% of patients studied by a panel of primary immunodeficiencies. Number of patients: 28. Only high quality variants are reported. -

Immunodeficiency 45 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Hepatitis B virus, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jun 13, 2006

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
Cadd	Benign	0.76
Dann	Benign	0.68
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0018	N
MetaRNN	Benign	0.0011	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.90	N;N;N;N;.
MutationTaster	Benign	1.0	P;P;P;P;P;P
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.68	N;N;N;N;N
REVEL	Benign	0.012
Sift	Benign	0.048	D;D;T;D;D
Sift4G	Benign	0.20	T;T;T;T;T
Polyphen		0.0010	B;B;B;B;.
Vest4		0.037
MPC		0.058
ClinPred		0.00058	T
GERP RS		-5.0
Varity_R		0.12
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs2229207; hg19: chr21-34614250; COSMIC: COSV59747161; COSMIC: COSV59747161;