12-25090181-G-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001366544.2(IRAG2):​c.590G>C​(p.Cys197Ser) variant causes a missense change. The variant allele was found at a frequency of 0.532 in 1,611,416 control chromosomes in the GnomAD database, including 234,185 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.46 (17793 hom., cov: 32)
  • Exomes 𝑓: 0.54 (216392 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.5913716E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.768 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRAG2	NM_001366544.2	c.590G>C	p.Cys197Ser	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>C	p.Cys197Ser	missense_variant	Exon 14 of 22	5	NM_001366544.2	ENSP00000451048.2

Frequencies

GnomAD3 genomes AF: 0.459 AC: 69750 AN: 151834 Hom.: 17786 Cov.: 32

Gnomad AFR AF: 0.227

Gnomad AMI AF: 0.421

Gnomad AMR AF: 0.495

Gnomad ASJ AF: 0.603

Gnomad EAS AF: 0.788

Gnomad SAS AF: 0.589

Gnomad FIN AF: 0.545

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.538

Gnomad OTH AF: 0.475

GnomAD2 exomes AF: 0.543 AC: 136117 AN: 250794 AF XY: 0.548

Gnomad AFR exome AF: 0.217

Gnomad AMR exome AF: 0.525

Gnomad ASJ exome AF: 0.602

Gnomad EAS exome AF: 0.782

Gnomad FIN exome AF: 0.561

Gnomad NFE exome AF: 0.535

Gnomad OTH exome AF: 0.547

GnomAD4 exome AF: 0.539 AC: 787277 AN: 1459464 Hom.: 216392 Cov.: 37 AF XY: 0.542 AC XY: 393380 AN XY: 726116

African (AFR) AF: 0.224 AC: 7477 AN: 33422

American (AMR) AF: 0.522 AC: 23335 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.602 AC: 15709 AN: 26108

East Asian (EAS) AF: 0.801 AC: 31778 AN: 39696

South Asian (SAS) AF: 0.583 AC: 50273 AN: 86194

European-Finnish (FIN) AF: 0.565 AC: 30129 AN: 53350

Middle Eastern (MID) AF: 0.518 AC: 2985 AN: 5762

European-Non Finnish (NFE) AF: 0.534 AC: 592950 AN: 1109946

Other (OTH) AF: 0.541 AC: 32641 AN: 60304

GnomAD4 genome AF: 0.459 AC: 69781 AN: 151952 Hom.: 17793 Cov.: 32 AF XY: 0.463 AC XY: 34390 AN XY: 74222

African (AFR) AF: 0.227 AC: 9415 AN: 41466

American (AMR) AF: 0.495 AC: 7564 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.603 AC: 2089 AN: 3466

East Asian (EAS) AF: 0.788 AC: 4079 AN: 5176

South Asian (SAS) AF: 0.588 AC: 2824 AN: 4806

European-Finnish (FIN) AF: 0.545 AC: 5727 AN: 10510

Middle Eastern (MID) AF: 0.514 AC: 151 AN: 294

European-Non Finnish (NFE) AF: 0.538 AC: 36549 AN: 67952

Other (OTH) AF: 0.475 AC: 1001 AN: 2106

Alfa AF: 0.525 Hom.: 15414

Bravo AF: 0.446

TwinsUK AF: 0.533 AC: 1976

ALSPAC AF: 0.536 AC: 2066

ESP6500AA AF: 0.230 AC: 1012

ESP6500EA AF: 0.532 AC: 4574

ExAC AF: 0.537 AC: 65210

Asia WGS AF: 0.659 AC: 2289 AN: 3478

EpiCase AF: 0.535

EpiControl AF: 0.537

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.34
CADD	Pathogenic	27
DANN	Uncertain	0.99
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.58	T;.;T;.;T
MetaRNN	Benign	0.0000026	T;T;T;T;T
MetaSVM	Benign	-0.92	T
PhyloP100		6.0
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-6.0	.;D;D;D;D
REVEL	Benign	0.22
Sift	Benign	0.074	.;T;T;T;T
Sift4G	Uncertain	0.014	.;D;D;D;D
Vest4		0.29, 0.24, 0.32, 0.30
MPC		0.94
ClinPred		0.028	T
GERP RS		5.8
PromoterAI		-0.00010	Neutral
gMVP		0.44
Mutation Taster		=100/0	polymorphism (auto)

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

dbSNP: rs1908946; hg19: chr12-25243115; COSMIC: COSV63138823; COSMIC: COSV63138823;