Genetic Variant NM_005534.4:c.206+2481T>C (chr21-33417501-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005534.4(IFNGR2):c.206+2481T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0939 in 152,284 control chromosomes in the GnomAD database, including 917 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.094 ( 917 hom., cov: 32)

Consequence

IFNGR2
NM_005534.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.155

Publications

11 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.237 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFNGR2	NM_005534.4 link	c.206+2481T>C		intron_variant	Intron 2 of 6	ENST00000290219.11	NP_005525.2
IFNGR2	NM_001329128.2 link	c.263+2481T>C		intron_variant	Intron 3 of 7		NP_001316057.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFNGR2	ENST00000290219.11 link	c.206+2481T>C		intron_variant	Intron 2 of 6	1	NM_005534.4	ENSP00000290219.5		P38484

Frequencies

GnomAD3 genomes

AF:

0.0938

AC:

14271

AN:

152166

Hom.:

911

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0311

Gnomad AMI

AF:

0.0833

Gnomad AMR

AF:

0.159

Gnomad ASJ

AF:

0.125

Gnomad EAS

AF:

0.248

Gnomad SAS

AF:

0.104

Gnomad FIN

AF:

0.0982

Gnomad MID

AF:

0.149

Gnomad NFE

AF:

0.102

Gnomad OTH

AF:

0.0944

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.0939

AC:

14295

AN:

152284

Hom.:

917

Cov.:

AF XY:

0.0957

AC XY:

7129

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.0311

AC:

1293

AN:

41568

American (AMR)

AF:

0.160

AC:

2439

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.125

AC:

434

AN:

3472

East Asian (EAS)

AF:

0.248

AC:

1286

AN:

5184

South Asian (SAS)

AF:

0.105

AC:

505

AN:

4826

European-Finnish (FIN)

AF:

0.0982

AC:

1042

AN:

10610

Middle Eastern (MID)

AF:

0.146

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.102

AC:

6963

AN:

68020

Other (OTH)

AF:

0.102

AC:

214

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

653

1306

1960

2613

3266

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

168

336

504

672

840

<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:

0.103

Hom.:

2585

Bravo

AF:

0.0979

Asia WGS

AF:

0.172

AC:

601

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

1.5

(source)

DANN

Benign

0.40

PhyloP100

-0.15

Mutation Taster

=100/0

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over