chr12-25101256-G-A

Variant names:

• chr12-25101256-G-A
• rs750930511
• NM_001366544.2:c.820G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001366544.2(IRAG2):​c.820G>A​(p.Ala274Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000548 in 1,460,020 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: IRAG2 NM_001366544.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.21

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRAG2	NM_001366544.2	c.820G>A	p.Ala274Thr	missense_variant	Exon 16 of 22	ENST00000556887.6	NP_001353473.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRAG2	ENST00000556887.6	c.820G>A	p.Ala274Thr	missense_variant	Exon 16 of 22	5	NM_001366544.2	ENSP00000451048.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1460020 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 726372

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.820G>A (p.A274T) alteration is located in exon 15 (coding exon 11) of the LRMP gene. This alteration results from a G to A substitution at nucleotide position 820, causing the alanine (A) at amino acid position 274 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
DANN	Pathogenic	1.0
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	D;.;D;.;D
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.46	T;T;T;T;T
MetaSVM	Benign	-0.87	T
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.2	.;D;D;D;D
REVEL	Benign	0.28
Sift	Uncertain	0.027	.;D;D;D;D
Sift4G	Uncertain	0.010	.;D;D;D;D
Vest4		0.31, 0.31, 0.31
MVP		0.51
MPC		0.62
ClinPred		0.99	D
GERP RS		4.6
gMVP		0.32

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

LitVar

Other links and lift over

dbSNP: rs750930511; hg19: chr12-25254190;