21-33403554-C-CGCTGCTGTGGTCGCTGCT

Variant names:

• chr21-33403554-C-CGCTGCTGTGGTCGCTGCT
• NM_005534.4:c.19_36dupTGGTCGCTGCTGCTGCTG

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_005534.4(IFNGR2):​c.19_36dupTGGTCGCTGCTGCTGCTG​(p.Trp7_Leu12dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000166 in 1,205,536 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L13L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: IFNGR2 NM_005534.4 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.128
• 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: Likely_benign. The variant received -1 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_005534.4

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.19_36dupTGGTCGCTGCTGCTGCTG	p.Trp7_Leu12dup	conservative_inframe_insertion	Exon 1 of 7	NP_005525.2
	IFNGR2	NM_001329128.2		c.19_36dupTGGTCGCTGCTGCTGCTG	p.Trp7_Leu12dup	conservative_inframe_insertion	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.19_36dupTGGTCGCTGCTGCTGCTG	p.Trp7_Leu12dup	conservative_inframe_insertion	Exon 1 of 7	ENSP00000290219.5	P38484
	IFNGR2	ENST00000964420.1		c.19_36dupTGGTCGCTGCTGCTGCTG	p.Trp7_Leu12dup	conservative_inframe_insertion	Exon 1 of 9	ENSP00000634479.1
	IFNGR2	ENST00000897490.1		c.19_36dupTGGTCGCTGCTGCTGCTG	p.Trp7_Leu12dup	conservative_inframe_insertion	Exon 1 of 8	ENSP00000567549.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000166 AC: 2 AN: 1205536 Hom.: 0 Cov.: 30 AF XY: 0.00000169 AC XY: 1 AN XY: 591600

African (AFR) AF: 0.00 AC: 0 AN: 24364

American (AMR) AF: 0.00 AC: 0 AN: 19824

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19410

East Asian (EAS) AF: 0.00 AC: 0 AN: 24706

South Asian (SAS) AF: 0.0000176 AC: 1 AN: 56934

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28060

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3328

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 981024

Other (OTH) AF: 0.0000209 AC: 1 AN: 47886

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
PhyloP100		-0.13

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr21-34775860;