chr21-33403580-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_005534.4(IFNGR2):c.37C>T(p.Leu13Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 1,375,618 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L13L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 4 hom. )

Consequence

IFNGR2
NM_005534.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 0.472

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

immunodeficiency 28
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
autosomal dominant mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR2 deficiency
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive Mendelian susceptibility to mycobacterial diseases due to complete IFNgammaR2 deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive Mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR2 deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

IFNGR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.071060866).

BP6

Variant 21-33403580-C-T is Benign according to our data. Variant chr21-33403580-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 474968.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00121 (183/151254) while in subpopulation AMR AF = 0.00329 (50/15210). AF 95% confidence interval is 0.00256. There are 1 homozygotes in GnomAd4. There are 77 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005534.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNGR2	NM_005534.4	MANE Select	c.37C>T	p.Leu13Phe	missense	Exon 1 of 7	NP_005525.2
	IFNGR2	NM_001329128.2		c.37C>T	p.Leu13Phe	missense	Exon 1 of 8	NP_001316057.1	E7EUY1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IFNGR2	ENST00000290219.11	TSL:1 MANE Select	c.37C>T	p.Leu13Phe	missense	Exon 1 of 7	ENSP00000290219.5	P38484
IFNGR2	ENST00000964420.1		c.37C>T	p.Leu13Phe	missense	Exon 1 of 9	ENSP00000634479.1
IFNGR2	ENST00000897490.1		c.37C>T	p.Leu13Phe	missense	Exon 1 of 8	ENSP00000567549.1

Frequencies

GnomAD3 genomes

AF:

0.00121

AC:

183

AN:

151146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000533

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00329

Gnomad ASJ

AF:

0.00116

Gnomad EAS

AF:

0.000195

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00148

Gnomad OTH

AF:

0.00240

GnomAD2 exomes

AF:

0.00126

AC:

AN:

60948

AF XY:

0.00122

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00178

Gnomad ASJ exome

AF:

0.000350

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000250

Gnomad NFE exome

AF:

0.00200

Gnomad OTH exome

AF:

0.00325

GnomAD4 exome

AF:

0.00163

AC:

1996

AN:

1224364

Hom.:

Cov.:

AF XY:

0.00154

AC XY:

928

AN XY:

601066

show subpopulations

African (AFR)

AF:

0.000243

AC:

AN:

24694

American (AMR)

AF:

0.00243

AC:

AN:

19788

Ashkenazi Jewish (ASJ)

AF:

0.000447

AC:

AN:

20144

East Asian (EAS)

AF:

0.000116

AC:

AN:

25932

South Asian (SAS)

AF:

0.000289

AC:

AN:

58722

European-Finnish (FIN)

AF:

0.0000690

AC:

AN:

28970

Middle Eastern (MID)

AF:

0.00116

AC:

AN:

3462

European-Non Finnish (NFE)

AF:

0.00186

AC:

1849

AN:

993452

Other (OTH)

AF:

0.00118

AC:

AN:

49200

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

193

290

386

483

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

156

234

312

390

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00121

AC:

183

AN:

151254

Hom.:

Cov.:

AF XY:

0.00104

AC XY:

AN XY:

73928

show subpopulations

African (AFR)

AF:

0.000531

AC:

AN:

41428

American (AMR)

AF:

0.00329

AC:

AN:

15210

Ashkenazi Jewish (ASJ)

AF:

0.00116

AC:

AN:

3462

East Asian (EAS)

AF:

0.000195

AC:

AN:

5122

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10238

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00148

AC:

100

AN:

67670

Other (OTH)

AF:

0.00238

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00111

Hom.:

Bravo

AF:

0.00190

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

IFNGR2-related disorder (1)

Immunodeficiency 28 (1)

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.12

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.41

M_CAP

Pathogenic

0.36

MetaRNN

Benign

0.071

MetaSVM

Benign

-0.59

MutationAssessor

Benign

1.5

PhyloP100

0.47

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.81

REVEL

Benign

0.18

Sift

Benign

0.20

Sift4G

Benign

0.25

Polyphen

1.0

Vest4

0.28

MVP

0.79

MPC

0.43

ClinPred

0.048

GERP RS

1.2

PromoterAI

0.024

Neutral

(source)

Varity_R

0.11

gMVP

0.25

Mutation Taster

=94/6

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over