21-33432729-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005534.4(IFNGR2):c.737A>G(p.Gln246Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: IFNGR2 NM_005534.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.99

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]

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26322502).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFNGR2	NM_005534.4	c.737A>G	p.Gln246Arg	missense_variant	6/7	ENST00000290219.11
IFNGR2	NM_001329128.2	c.794A>G	p.Gln265Arg	missense_variant	7/8
TMEM50B	XM_011529746.3	c.*2304T>C		3_prime_UTR_variant	10/10
TMEM50B	NR_040016.2	n.2849T>C		non_coding_transcript_exon_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFNGR2	ENST00000290219.11	c.737A>G	p.Gln246Arg	missense_variant	6/7	1	NM_005534.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461876 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 727236

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 28, 2023

The c.737A>G (p.Q246R) alteration is located in exon 6 (coding exon 6) of the IFNGR2 gene. This alteration results from a A to G substitution at nucleotide position 737, causing the glutamine (Q) at amino acid position 246 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Benign	-0.26
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.17	T;.;.
Eigen	Benign	-0.011
Eigen_PC	Benign	-0.058
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.72	T;T;T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Uncertain	2.2	M;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.0	N;N;N
REVEL	Benign	0.21
Sift	Benign	0.24	T;T;T
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.95	P;P;.
Vest4		0.30
MutPred		0.40		.;Gain of relative solvent accessibility (P = 0.1259);.;
MVP		0.81
MPC		1.2
ClinPred		0.94	D
GERP RS		5.4
Varity_R		0.14
gMVP		0.54

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

Other links and lift over

dbSNP: rs2083901482; hg19: chr21-34805036;