rs1908946

Variant names:

• chr12-25090181-G-A
• rs1908946
• NM_001366544.2:c.590G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-25090181-G-A
• chr12-25090181-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001366544.2(IRAG2):​c.590G>A​(p.Cys197Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,613,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: IRAG2 NM_001366544.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.02
• Publications: 36 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.796

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRAG2	NM_001366544.2	c.590G>A	p.Cys197Tyr	missense_variant	Exon 14 of 22	ENST00000556887.6	NP_001353473.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRAG2	ENST00000556887.6	c.590G>A	p.Cys197Tyr	missense_variant	Exon 14 of 22	5	NM_001366544.2	ENSP00000451048.2

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151900 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461324 Hom.: 0 Cov.: 37 AF XY: 0.00000138 AC XY: 1 AN XY: 726994

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111578

Other (OTH) AF: 0.00 AC: 0 AN: 60368

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151900 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74134

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41368

American (AMR) AF: 0.00 AC: 0 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67976

Other (OTH) AF: 0.00 AC: 0 AN: 2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000203), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 15414

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.87	D;.;D;.;D
M_CAP	Benign	0.0092	T
MetaRNN	Pathogenic	0.80	D;D;D;D;D
MetaSVM	Benign	-0.38	T
PhyloP100		6.0
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-6.7	.;D;D;D;D
REVEL	Uncertain	0.36
Sift	Benign	0.072	.;T;T;T;T
Sift4G	Uncertain	0.0020	.;D;D;D;D
Vest4		0.59, 0.57, 0.58, 0.59
MVP		0.27
MPC		1.1
ClinPred		0.95	D
GERP RS		5.8
PromoterAI		0.0090	Neutral
gMVP		0.54
Mutation Taster		=42/58	disease causing

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

Other links and lift over

dbSNP: rs1908946; hg19: chr12-25243115;