21-33432706-C-CT

Variant names:

• chr21-33432706-C-CT
• NM_005534.4:c.722-3dupT

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 6P and 2B. PVS1_Strong PM2 BP6_Moderate

The NM_005534.4(IFNGR2):​c.722-3dupT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: IFNGR2 NM_005534.4 splice_acceptor, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.451
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.15581854 fraction of the gene. Cryptic splice site detected, with MaxEntScore 9.9, offset of 0 (no position change), new splice context is: tttcgtgtcctcttttttAGcct. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 21-33432706-C-CT is Benign according to our data. Variant chr21-33432706-C-CT is described in ClinVar as Benign. ClinVar VariationId is 3627292.Status of the report is criteria_provided_single_submitter, 1 stars.

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.722-3dupT		splice_acceptor intron	N/A	NP_005525.2
	IFNGR2	NM_001329128.2		c.779-3dupT		splice_acceptor intron	N/A	NP_001316057.1	E7EUY1
	TMEM50B	NR_040016.2		n.2871dupA		non_coding_transcript_exon	Exon 9 of 9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNGR2	ENST00000290219.11	TSL:1 MANE Select	c.722-3dupT		splice_acceptor intron	N/A	ENSP00000290219.5	P38484
	TMEM50B	ENST00000420455.5	TSL:1	n.*2216dupA		non_coding_transcript_exon	Exon 9 of 9	ENSP00000397773.1	P56557
	TMEM50B	ENST00000420455.5	TSL:1	n.*2216dupA		3_prime_UTR	Exon 9 of 9	ENSP00000397773.1	P56557

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Benign

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		0.45

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

hg19: chr21-34805013;