Genetic Variant IRAG2:p.Ala274Pro (chr12-25101256-G-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001366544.2(IRAG2):c.820G>C(p.Ala274Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,460,020 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. A274T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

IRAG2
NM_001366544.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.21

Publications

1 publications found

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]

IRAG2 links:

ENSG00000298872 (HGNC:):

ENSG00000298872 links:

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ACMG classification

Classification was made for transcript

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, 0.813

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IRAG2	NM_001366544.2	MANE Select	c.820G>C	p.Ala274Pro	missense	Exon 16 of 22	NP_001353473.1	Q12912-2
IRAG2	NM_001394803.1		c.3661G>C	p.Ala1221Pro	missense	Exon 34 of 40	NP_001381732.1
IRAG2	NM_001204126.2		c.820G>C	p.Ala274Pro	missense	Exon 14 of 20	NP_001191055.1	Q12912-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IRAG2	ENST00000556887.6	TSL:5 MANE Select	c.820G>C	p.Ala274Pro	missense	Exon 16 of 22	ENSP00000451048.2	Q12912-2
IRAG2	ENST00000354454.7	TSL:1	c.820G>C	p.Ala274Pro	missense	Exon 15 of 21	ENSP00000346442.3	Q12912-2
IRAG2	ENST00000547044.5	TSL:1	c.820G>C	p.Ala274Pro	missense	Exon 14 of 20	ENSP00000450246.1	Q12912-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

250428

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1460020

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726372

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33426

American (AMR)

AF:

0.0000224

AC:

AN:

44628

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26062

East Asian (EAS)

AF:

0.00

AC:

AN:

39596

South Asian (SAS)

AF:

0.00

AC:

AN:

86088

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53338

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1110828

Other (OTH)

AF:

0.00

AC:

AN:

60296

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.10

CADD

Uncertain

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.067

MetaRNN

Pathogenic

0.81

MetaSVM

Benign

-0.67

PhyloP100

5.2

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-4.1

REVEL

Uncertain

0.55

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.012

Vest4

0.78

MVP

0.49

MPC

0.97

ClinPred

0.99

GERP RS

4.6

gMVP

0.76

Mutation Taster

=21/79

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over