rs17885407

Positions:

• chr21-33436926-G-A
• chrNW_003315970.2-31498-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The ENST00000290219.11(IFNGR2):​c.978G>A​(p.Pro326=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00261 in 1,613,946 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (10 hom.)
• Consequence: IFNGR2 ENST00000290219.11 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.58

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 Benign. Variant got -16 ACMG points.

• BP6: Variant 21-33436926-G-A is Benign according to our data. Variant chr21-33436926-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 474971.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00178 (270/152106) while in subpopulation NFE AF= 0.00337 (229/67994). AF 95% confidence interval is 0.00301. There are 2 homozygotes in gnomad4. There are 99 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFNGR2	NM_005534.4	c.978G>A	p.Pro326=	synonymous_variant	7/7	ENST00000290219.11	NP_005525.2
IFNGR2	NM_001329128.2	c.1035G>A	p.Pro345=	synonymous_variant	8/8		NP_001316057.1
TMEM50B	XM_011529746.3	c.*2187C>T		3_prime_UTR_variant	9/10		XP_011528048.1
TMEM50B	NR_040016.2	n.2775+2288C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFNGR2	ENST00000290219.11	c.978G>A	p.Pro326=	synonymous_variant	7/7	1	NM_005534.4	ENSP00000290219	P1

Frequencies

GnomAD3 genomes AF: 0.00178 AC: 270 AN: 151988 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000508

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000591

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000567

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00337

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00138 AC: 346 AN: 251236 Hom.: 0 AF XY: 0.00124 AC XY: 169 AN XY: 135782

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000555

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00262

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00270 AC: 3942 AN: 1461840 Hom.: 10 Cov.: 31 AF XY: 0.00261 AC XY: 1900 AN XY: 727226

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000614

Gnomad4 FIN exome AF: 0.000543

Gnomad4 NFE exome AF: 0.00336

Gnomad4 OTH exome AF: 0.00154

GnomAD4 genome AF: 0.00178 AC: 270 AN: 152106 Hom.: 2 Cov.: 32 AF XY: 0.00133 AC XY: 99 AN XY: 74376

Gnomad4 AFR AF: 0.000506

Gnomad4 AMR AF: 0.000590

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.000567

Gnomad4 NFE AF: 0.00337

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00259 Hom.: 1

Bravo AF: 0.00162

EpiCase AF: 0.00344

EpiControl AF: 0.00249

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Immunodeficiency 28 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

IFNGR2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 12, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	18
DANN	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.43		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.43		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs17885407; hg19: chr21-34809233;