chr21-33403596-C-T

Position:

chr21-33403596-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_005534.4(IFNGR2):c.53C>T(p.Ala18Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000117 in 1,371,460 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 1 hom. )

Consequence

IFNGR2
NM_005534.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.249

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.026349008).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000119 (18/151330) while in subpopulation NFE AF= 0.000192 (13/67742). AF 95% confidence interval is 0.000113. There are 0 homozygotes in gnomad4. There are 6 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFNGR2	NM_005534.4 linkuse as main transcript	c.53C>T	p.Ala18Val	missense_variant	1/7	ENST00000290219.11	NP_005525.2
IFNGR2	NM_001329128.2 linkuse as main transcript	c.53C>T	p.Ala18Val	missense_variant	1/8		NP_001316057.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFNGR2	ENST00000290219.11 linkuse as main transcript	c.53C>T	p.Ala18Val	missense_variant	1/7	1	NM_005534.4	ENSP00000290219	P1

Frequencies

GnomAD3 genomes

AF:

0.000119

AC:

AN:

151330

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000192

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.000211

AC:

AN:

52090

Hom.:

AF XY:

0.000194

AC XY:

AN XY:

30910

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00142

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000211

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000117

AC:

143

AN:

1220130

Hom.:

Cov.:

AF XY:

0.000125

AC XY:

AN XY:

598310

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00147

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000695

Gnomad4 NFE exome

AF:

0.000103

Gnomad4 OTH exome

AF:

0.000203

GnomAD4 genome

AF:

0.000119

AC:

AN:

151330

Hom.:

Cov.:

AF XY:

0.0000812

AC XY:

AN XY:

73894

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000192

Gnomad4 OTH

AF:

0.000480

Alfa

AF:

0.000108

Hom.:

Bravo

AF:

0.000125

ExAC

AF:

0.000166

AC:

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

Labcorp Genetics (formerly Invitae), Labcorp

Aug 19, 2022

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 18 of the IFNGR2 protein (p.Ala18Val). This variant is present in population databases (rs773932279, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with IFNGR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 863856). 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: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.47

CADD

Benign

8.2

DANN

Benign

0.87

DEOGEN2

Benign

0.099

T;.

Eigen

Benign

-0.77

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.0040

LIST_S2

Benign

0.48

T;T

M_CAP

Benign

0.010

MetaRNN

Benign

0.026

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.1

L;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Uncertain

0.53

PROVEAN

Benign

0.030

N;N

REVEL

Benign

0.055

Sift

Benign

0.14

T;T

Sift4G

Benign

0.087

T;D

Polyphen

0.90

P;P

Vest4

0.26

MutPred

0.33

Loss of helix (P = 0.028);Loss of helix (P = 0.028);

MVP

0.72

MPC

0.40

ClinPred

0.11

GERP RS

0.22

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Varity_R

0.095

gMVP

0.27

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