21-33403128-A-C

Variant names:

• chr21-33403128-A-C
• rs8134145
• NM_001329128.2:c.-416A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001329128.2(IFNGR2):​c.-416A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.249 in 143,450 control chromosomes in the GnomAD database, including 5,891 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5889 hom., cov: 26)
  • Exomes 𝑓: 0.10 (2 hom.)
• Consequence: IFNGR2 NM_001329128.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.45
• Publications: 8 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

ENSG00000289939 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 21-33403128-A-C is Benign according to our data. Variant chr21-33403128-A-C is described in ClinVar as Benign. ClinVar VariationId is 1232698.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.457 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNGR2	NM_001329128.2		c.-416A>C		5_prime_UTR	Exon 1 of 8	NP_001316057.1	E7EUY1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNGR2	ENST00000964419.1		c.-416A>C		upstream_gene	N/A	ENSP00000634478.1
	ENSG00000289939	ENST00000701889.2		n.*81A>C		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.249 AC: 35737 AN: 143310 Hom.: 5874 Cov.: 26

Gnomad AFR AF: 0.462

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.187

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.428

Gnomad SAS AF: 0.298

Gnomad FIN AF: 0.209

Gnomad MID AF: 0.113

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.211

GnomAD4 exome AF: 0.102 AC: 9 AN: 88 Hom.: 2 Cov.: 0 AF XY: 0.0938 AC XY: 6 AN XY: 64

African (AFR) AF: 0.750 AC: 3 AN: 4

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6

East Asian (EAS) AF: 1.00 AC: 2 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0606 AC: 4 AN: 66

Other (OTH) AF: 0.00 AC: 0 AN: 4

GnomAD4 genome AF: 0.250 AC: 35777 AN: 143362 Hom.: 5889 Cov.: 26 AF XY: 0.252 AC XY: 17495 AN XY: 69520

African (AFR) AF: 0.462 AC: 18031 AN: 38992

American (AMR) AF: 0.186 AC: 2640 AN: 14170

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 437 AN: 3308

East Asian (EAS) AF: 0.428 AC: 2121 AN: 4956

South Asian (SAS) AF: 0.297 AC: 1341 AN: 4516

European-Finnish (FIN) AF: 0.209 AC: 1939 AN: 9294

Middle Eastern (MID) AF: 0.125 AC: 35 AN: 280

European-Non Finnish (NFE) AF: 0.134 AC: 8728 AN: 65006

Other (OTH) AF: 0.208 AC: 409 AN: 1964

Alfa AF: 0.176 Hom.: 437

Bravo AF: 0.252

Asia WGS AF: 0.362 AC: 1204 AN: 3338

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	5.8
DANN	Benign	0.63
PhyloP100		-1.4
PromoterAI		-0.0059	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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: rs8134145; hg19: chr21-34775434;