12-25104363-G-C

Variant names:

• chr12-25104363-G-C
• rs775148882
• NM_001366544.2:c.1049G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001366544.2(IRAG2):​c.1049G>C​(p.Arg350Pro) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000693 in 1,444,000 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R350H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: IRAG2 NM_001366544.2 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.63
• Publications: 0 publications found

Genes affected

IRAG2 (HGNC:6690): (inositol 1,4,5-triphosphate receptor associated 2) The protein encode dby this gene is expressed in a developmentally regulated manner in lymphoid cell lines and tissues. The protein is localized to the cytoplasmic face of the endoplasmic reticulum. [provided by RefSeq, Jul 2008]

ENSG00000298872 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001366544.2. 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
	IRAG2	NM_001366544.2	MANE Select	c.1049G>C	p.Arg350Pro	missense splice_region	Exon 20 of 22	NP_001353473.1	Q12912-2
	IRAG2	NM_001394803.1		c.3890G>C	p.Arg1297Pro	missense splice_region	Exon 38 of 40	NP_001381732.1
	IRAG2	NM_001204126.2		c.1049G>C	p.Arg350Pro	missense splice_region	Exon 18 of 20	NP_001191055.1	Q12912-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRAG2	ENST00000556887.6	TSL:5 MANE Select	c.1049G>C	p.Arg350Pro	missense splice_region	Exon 20 of 22	ENSP00000451048.2	Q12912-2
	IRAG2	ENST00000354454.7	TSL:1	c.1049G>C	p.Arg350Pro	missense splice_region	Exon 19 of 21	ENSP00000346442.3	Q12912-2
	IRAG2	ENST00000547044.5	TSL:1	c.1049G>C	p.Arg350Pro	missense splice_region	Exon 18 of 20	ENSP00000450246.1	Q12912-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1444000 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 719558

African (AFR) AF: 0.00 AC: 0 AN: 33110

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26032

East Asian (EAS) AF: 0.00 AC: 0 AN: 39554

South Asian (SAS) AF: 0.00 AC: 0 AN: 85890

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 9.13e-7 AC: 1 AN: 1095782

Other (OTH) AF: 0.00 AC: 0 AN: 59788

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Benign	-0.00099	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	29
DANN	Uncertain	1.0
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-0.88	T
PhyloP100		3.6
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.19
Sift	Uncertain	0.012	D
Sift4G	Benign	0.14	T
Vest4		0.27
MVP		0.35
MPC		1.0
ClinPred		0.94	D
GERP RS		5.4
gMVP		0.31
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs775148882; hg19: chr12-25257297;