12-25069423-A-C

Variant names:

• chr12-25069423-A-C
• rs755476102
• NM_001366544.2:c.16A>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001366544.2(IRAG2):​c.16A>C​(p.Ser6Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000589 in 1,613,958 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S6N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000063 (2 hom.)
• Consequence: IRAG2 NM_001366544.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.917
• Publications: 0 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]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.047190964).
• BS2: High Homozygotes in GnomAdExome4 at 2 gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRAG2	NM_001366544.2	MANE Select	c.16A>C	p.Ser6Arg	missense	Exon 6 of 22	NP_001353473.1	Q12912-2
	IRAG2	NM_001394803.1		c.2857A>C	p.Ser953Arg	missense	Exon 24 of 40	NP_001381732.1
	IRAG2	NM_001204126.2		c.16A>C	p.Ser6Arg	missense	Exon 4 of 20	NP_001191055.1	Q12912-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRAG2	ENST00000556887.6	TSL:5 MANE Select	c.16A>C	p.Ser6Arg	missense	Exon 6 of 22	ENSP00000451048.2	Q12912-2
	IRAG2	ENST00000354454.7	TSL:1	c.16A>C	p.Ser6Arg	missense	Exon 5 of 21	ENSP00000346442.3	Q12912-2
	IRAG2	ENST00000547044.5	TSL:1	c.16A>C	p.Ser6Arg	missense	Exon 4 of 20	ENSP00000450246.1	Q12912-2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152190 Hom.: 1 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: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000358 AC: 9 AN: 251368 AF XY: 0.0000515

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000629 AC: 92 AN: 1461768 Hom.: 2 Cov.: 30 AF XY: 0.0000853 AC XY: 62 AN XY: 727194

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.000359 AC: 31 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0000432 AC: 48 AN: 1111920

Other (OTH) AF: 0.000149 AC: 9 AN: 60392

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152190 Hom.: 1 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74362

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15276

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

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

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.0000151

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	7.4
DANN	Benign	0.94
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.0016	T
MetaRNN	Benign	0.047	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.92
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.014
Sift	Benign	0.21	T
Sift4G	Benign	0.55	T
Vest4		0.16
MVP		0.076
MPC		0.26
ClinPred		0.057	T
GERP RS		-0.55
gMVP		0.056
Mutation Taster		=92/8	polymorphism

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: rs755476102; hg19: chr12-25222357;