21-33426974-C-T

Variant names:

• chr21-33426974-C-T
• rs74315444
• NM_005534.4:c.503C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_001329128.2(IFNGR2):​c.560C>T​(p.Thr187Ile) 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 1,461,306 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T187N) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: IFNGR2 NM_001329128.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.461
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-33426974-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 14727.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.078492135).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001329128.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNGR2	NM_005534.4	MANE Select	c.503C>T	p.Thr168Ile	missense	Exon 4 of 7	NP_005525.2
	IFNGR2	NM_001329128.2		c.560C>T	p.Thr187Ile	missense	Exon 5 of 8	NP_001316057.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNGR2	ENST00000290219.11	TSL:1 MANE Select	c.503C>T	p.Thr168Ile	missense	Exon 4 of 7	ENSP00000290219.5
	IFNGR2	ENST00000964420.1		c.653C>T	p.Thr218Ile	missense	Exon 6 of 9	ENSP00000634479.1
	IFNGR2	ENST00000897490.1		c.596C>T	p.Thr199Ile	missense	Exon 5 of 8	ENSP00000567549.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461306 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726992

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111484

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.065
DANN	Benign	0.92
DEOGEN2	Benign	0.085	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.078	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		-0.46
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.020
Sift	Benign	0.20	T
Sift4G	Benign	0.17	T
Polyphen		0.040	B
Vest4		0.084
MutPred		0.41		Loss of glycosylation at S188 (P = 0.1013)
MVP		0.39
MPC		0.67
ClinPred		0.12	T
GERP RS		-8.0
Varity_R		0.18
gMVP		0.20
Mutation Taster		=53/47	polymorphism

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

Other links and lift over

dbSNP: rs74315444; hg19: chr21-34799281; COSMIC: COSV51638171;