21-33436926-G-T

Variant names:

• chr21-33436926-G-T
• NM_005534.4:c.978G>T
• IFNGR2 p.Pro326Pro

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_005534.4(IFNGR2):​c.978G>T​(p.Pro326Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P326P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IFNGR2 NM_005534.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.58
• 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]

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

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP7: Synonymous conserved (PhyloP=1.58 with no splicing effect.

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.978G>T	p.Pro326Pro	synonymous	Exon 7 of 7	NP_005525.2
	IFNGR2	NM_001329128.2		c.1035G>T	p.Pro345Pro	synonymous	Exon 8 of 8	NP_001316057.1	E7EUY1
	TMEM50B	NR_040016.2		n.2775+2288C>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNGR2	ENST00000290219.11	TSL:1 MANE Select	c.978G>T	p.Pro326Pro	synonymous	Exon 7 of 7	ENSP00000290219.5	P38484
	TMEM50B	ENST00000420455.5	TSL:1	n.*2120+2288C>A		intron	N/A	ENSP00000397773.1	P56557
	IFNGR2	ENST00000964420.1		c.1128G>T	p.Pro376Pro	synonymous	Exon 9 of 9	ENSP00000634479.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	3.3
DANN	Benign	0.67
PhyloP100		1.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr21-34809233;