rs1555878402

Variant names:

• chr21-33403608-C-T
• rs1555878402
• NM_005534.4:c.65C>T

Your query was ambiguous. Multiple possible variants found:

• chr21-33403608-C-T
• chr21-33403608-C-A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005534.4(IFNGR2):​c.65C>T​(p.Ala22Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000165 in 1,215,246 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: IFNGR2 NM_005534.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.434
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.060047716).

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.65C>T	p.Ala22Val	missense	Exon 1 of 7	NP_005525.2
	IFNGR2	NM_001329128.2		c.65C>T	p.Ala22Val	missense	Exon 1 of 8	NP_001316057.1	E7EUY1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNGR2	ENST00000290219.11	TSL:1 MANE Select	c.65C>T	p.Ala22Val	missense	Exon 1 of 7	ENSP00000290219.5	P38484
	IFNGR2	ENST00000964420.1		c.65C>T	p.Ala22Val	missense	Exon 1 of 9	ENSP00000634479.1
	IFNGR2	ENST00000897490.1		c.65C>T	p.Ala22Val	missense	Exon 1 of 8	ENSP00000567549.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000165 AC: 2 AN: 1215246 Hom.: 0 Cov.: 31 AF XY: 0.00000168 AC XY: 1 AN XY: 595450

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 24372

American (AMR) AF: 0.00 AC: 0 AN: 17832

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19324

East Asian (EAS) AF: 0.0000380 AC: 1 AN: 26322

South Asian (SAS) AF: 0.0000178 AC: 1 AN: 56314

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28548

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3426

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 990028

Other (OTH) AF: 0.00 AC: 0 AN: 49080

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00666416), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Immunodeficiency 28 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	10
DANN	Benign	0.87
DEOGEN2	Benign	0.085	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.060	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.49	N
PhyloP100		0.43
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.11	N
REVEL	Benign	0.056
Sift	Benign	0.32	T
Sift4G	Benign	0.31	T
Polyphen		0.0	B
Vest4		0.14
MutPred		0.34		Gain of sheet (P = 0.0266)
MVP		0.47
MPC		0.40
ClinPred		0.15	T
GERP RS		-0.83
PromoterAI		-0.10	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Varity_R		0.055
gMVP		0.30
Mutation Taster		=98/2	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: rs1555878402; hg19: chr21-34775914;