21-33432753-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_005534.4(IFNGR2):c.761G>A(p.Gly254Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G254V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

IFNGR2
NM_005534.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.34

Variant links:

Genes affected

IFNGR2 (HGNC:5440): (interferon gamma receptor 2) This gene (IFNGR2) encodes the non-ligand-binding beta chain of the gamma interferon receptor. Human interferon-gamma receptor is a heterodimer of IFNGR1 and IFNGR2. Defects in IFNGR2 are a cause of mendelian susceptibility to mycobacterial disease (MSMD), also known as familial disseminated atypical mycobacterial infection. MSMD is a genetically heterogeneous disease with autosomal recessive, autosomal dominant or X-linked inheritance. [provided by RefSeq, Jul 2008]

IFNGR2 links:

TMEM50B (HGNC:1280): (transmembrane protein 50B) Predicted to be involved in late endosome to vacuole transport via multivesicular body sorting pathway. Located in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

TMEM50B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.826

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
IFNGR2	NM_005534.4 linkuse as main transcript	c.761G>A	p.Gly254Glu	missense_variant	6/7	ENST00000290219.11
IFNGR2	NM_001329128.2 linkuse as main transcript	c.818G>A	p.Gly273Glu	missense_variant	7/8
TMEM50B	XM_011529746.3 linkuse as main transcript	c.*2280C>T		3_prime_UTR_variant	10/10
TMEM50B	NR_040016.2 linkuse as main transcript	n.2825C>T		non_coding_transcript_exon_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFNGR2	ENST00000290219.11 linkuse as main transcript	c.761G>A	p.Gly254Glu	missense_variant	6/7	1	NM_005534.4	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Immunodeficiency 28

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 12, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals affected with IFNGR2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 254 of the IFNGR2 protein (p.Gly254Glu). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.69

D;.;.

Eigen

Benign

0.056

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.77

T;T;T

M_CAP

Benign

0.051

MetaRNN

Pathogenic

0.83

D;D;D

MetaSVM

Benign

-0.68

MutationAssessor

Uncertain

2.2

M;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.42

PROVEAN

Pathogenic

-4.6

D;D;D

REVEL

Uncertain

0.36

Sift

Uncertain

0.0050

D;D;D

Sift4G

Uncertain

0.049

D;D;T

Polyphen

1.0

D;D;.

Vest4

0.69

MutPred

0.62

.;Gain of sheet (P = 0.0344);.;

MVP

0.83

MPC

1.4

ClinPred

0.96

GERP RS

3.1

Varity_R

0.45

gMVP

0.84

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over