12-25101185-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001366544.2(IRAG2):​c.749G>T​(p.Arg250Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,443,276 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R250Q) 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

Scores

10
4
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.25
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.88

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
IRAG2NM_001366544.2 linkc.749G>T p.Arg250Leu missense_variant Exon 16 of 22 ENST00000556887.6 NP_001353473.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
IRAG2ENST00000556887.6 linkc.749G>T p.Arg250Leu missense_variant Exon 16 of 22 5 NM_001366544.2 ENSP00000451048.2 Q12912-2A0A0G2JL87

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.93e-7
AC:
1
AN:
1443276
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
717514
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.07e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.29
D
BayesDel_noAF
Pathogenic
0.17
CADD
Pathogenic
31
DANN
Uncertain
1.0
Eigen
Pathogenic
0.89
Eigen_PC
Pathogenic
0.86
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Pathogenic
0.97
D;.;D;.;D
M_CAP
Uncertain
0.093
D
MetaRNN
Pathogenic
0.88
D;D;D;D;D
MetaSVM
Benign
-0.62
T
PrimateAI
Uncertain
0.75
T
PROVEAN
Pathogenic
-5.8
.;D;D;D;D
REVEL
Pathogenic
0.81
Sift
Pathogenic
0.0
.;D;D;D;D
Sift4G
Pathogenic
0.0
.;D;D;D;D
Vest4
0.97, 0.98, 0.96, 0.97
MVP
0.73
MPC
0.95
ClinPred
1.0
D
GERP RS
5.5
gMVP
0.81

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-25254119; COSMIC: COSV100611919; COSMIC: COSV100611919; API