NM_001366544.2:c.421C>A

Variant names:

• chr12-25089661-C-A
• rs7969931
• NM_001366544.2:c.421C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001366544.2(IRAG2):​c.421C>A​(p.Leu141Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000872 in 1,605,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: IRAG2 NM_001366544.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.788
• Publications: 39 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06865108).

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.421C>A	p.Leu141Ile	missense	Exon 12 of 22	NP_001353473.1	Q12912-2
	IRAG2	NM_001394803.1		c.3262C>A	p.Leu1088Ile	missense	Exon 30 of 40	NP_001381732.1
	IRAG2	NM_001204126.2		c.421C>A	p.Leu141Ile	missense	Exon 10 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.421C>A	p.Leu141Ile	missense	Exon 12 of 22	ENSP00000451048.2	Q12912-2
	IRAG2	ENST00000354454.7	TSL:1	c.421C>A	p.Leu141Ile	missense	Exon 11 of 21	ENSP00000346442.3	Q12912-2
	IRAG2	ENST00000547044.5	TSL:1	c.421C>A	p.Leu141Ile	missense	Exon 10 of 20	ENSP00000450246.1	Q12912-2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152058 Hom.: 0 Cov.: 33

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 250848 AF XY: 0.0000295

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: 0.00000895 AC: 13 AN: 1452976 Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 10 AN XY: 723430

African (AFR) AF: 0.00 AC: 0 AN: 33298

American (AMR) AF: 0.00 AC: 0 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26076

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39640

South Asian (SAS) AF: 0.0000349 AC: 3 AN: 86000

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5622

European-Non Finnish (NFE) AF: 0.00000543 AC: 6 AN: 1104258

Other (OTH) AF: 0.0000167 AC: 1 AN: 60012

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152058 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74244

African (AFR) AF: 0.00 AC: 0 AN: 41368

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10568

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 31056

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	17
DANN	Benign	0.95
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.069	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.79
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	0.040	N
REVEL	Benign	0.061
Sift	Benign	0.066	T
Sift4G	Benign	0.24	T
Vest4		0.093
MVP		0.16
MPC		0.25
ClinPred		0.091	T
GERP RS		4.3
PromoterAI		-0.021	Neutral
gMVP		0.062
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs7969931; hg19: chr12-25242595;