12-25089661-C-G

Position:

• chr12-25089661-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001366544.2(IRAG2):​c.421C>G​(p.Leu141Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.75 in 1,601,444 control chromosomes in the GnomAD database, including 453,345 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.72 (39777 hom., cov: 33)
  • Exomes 𝑓: 0.75 (413568 hom.)
• Consequence: IRAG2 NM_001366544.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.788

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.7191794E-7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.859 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRAG2	NM_001366544.2	c.421C>G	p.Leu141Val	missense_variant	12/22	ENST00000556887.6	NP_001353473.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRAG2	ENST00000556887.6	c.421C>G	p.Leu141Val	missense_variant	12/22	5	NM_001366544.2	ENSP00000451048

Frequencies

GnomAD3 genomes AF: 0.719 AC: 109225 AN: 151996 Hom.: 39757 Cov.: 33

Gnomad AFR AF: 0.611

Gnomad AMI AF: 0.884

Gnomad AMR AF: 0.747

Gnomad ASJ AF: 0.870

Gnomad EAS AF: 0.880

Gnomad SAS AF: 0.734

Gnomad FIN AF: 0.642

Gnomad MID AF: 0.823

Gnomad NFE AF: 0.765

Gnomad OTH AF: 0.746

GnomAD3 exomes AF: 0.748 AC: 187678 AN: 250848 Hom.: 70887 AF XY: 0.750 AC XY: 101756 AN XY: 135606

Gnomad AFR exome AF: 0.607

Gnomad AMR exome AF: 0.711

Gnomad ASJ exome AF: 0.869

Gnomad EAS exome AF: 0.882

Gnomad SAS exome AF: 0.727

Gnomad FIN exome AF: 0.660

Gnomad NFE exome AF: 0.768

Gnomad OTH exome AF: 0.768

GnomAD4 exome AF: 0.753 AC: 1091964 AN: 1449330 Hom.: 413568 Cov.: 33 AF XY: 0.754 AC XY: 543925 AN XY: 721756

Gnomad4 AFR exome AF: 0.600

Gnomad4 AMR exome AF: 0.716

Gnomad4 ASJ exome AF: 0.870

Gnomad4 EAS exome AF: 0.895

Gnomad4 SAS exome AF: 0.725

Gnomad4 FIN exome AF: 0.672

Gnomad4 NFE exome AF: 0.757

Gnomad4 OTH exome AF: 0.762

GnomAD4 genome AF: 0.718 AC: 109284 AN: 152114 Hom.: 39777 Cov.: 33 AF XY: 0.717 AC XY: 53288 AN XY: 74340

Gnomad4 AFR AF: 0.610

Gnomad4 AMR AF: 0.747

Gnomad4 ASJ AF: 0.870

Gnomad4 EAS AF: 0.880

Gnomad4 SAS AF: 0.734

Gnomad4 FIN AF: 0.642

Gnomad4 NFE AF: 0.765

Gnomad4 OTH AF: 0.748

Alfa AF: 0.768 Hom.: 31056

Bravo AF: 0.720

TwinsUK AF: 0.750 AC: 2780

ALSPAC AF: 0.754 AC: 2907

ESP6500AA AF: 0.610 AC: 2686

ESP6500EA AF: 0.763 AC: 6566

ExAC AF: 0.745 AC: 90471

Asia WGS AF: 0.822 AC: 2858 AN: 3478

EpiCase AF: 0.771

EpiControl AF: 0.778

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	16
DANN	Benign	0.89
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.47
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.12	T;.;T;.;T
MetaRNN	Benign	7.7e-7	T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-0.25	.;N;N;N;N
REVEL	Benign	0.091
Sift	Benign	0.19	.;T;T;T;T
Sift4G	Benign	0.29	.;T;T;T;T
Vest4		0.025, 0.016, 0.014
MPC		0.24
ClinPred		0.0019	T
GERP RS		4.3
gMVP		0.088

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

Publications

LitVar

Other links and lift over

dbSNP: rs7969931; hg19: chr12-25242595; COSMIC: COSV63139784; COSMIC: COSV63139784;