Variant 12-121626750-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_032790.3(ORAI1):c.8C>T(p.Pro3Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000187 in 1,067,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000019 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ORAI1
NM_032790.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.34

Variant links:

Genes affected

ORAI1 (HGNC:25896): (ORAI calcium release-activated calcium modulator 1) The protein encoded by this gene is a membrane calcium channel subunit that is activated by the calcium sensor STIM1 when calcium stores are depleted. This type of channel is the primary way for calcium influx into T-cells. Defects in this gene are a cause of immune dysfunction with T-cell inactivation due to calcium entry defect type 1 (IDTICED1). [provided by RefSeq, Sep 2011]

ORAI1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23516801).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ORAI1	NM_032790.3 linkuse as main transcript	c.8C>T	p.Pro3Leu	missense_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	Appris	UniProt
ORAI1	ENST00000617316.2 linkuse as main transcript	c.8C>T	p.Pro3Leu	missense_variant	1/3	1	P1	Q96D31-1
ORAI1	ENST00000646827.1 linkuse as main transcript	n.201C>T		non_coding_transcript_exon_variant	1/2
ORAI1	ENST00000698901.1 linkuse as main transcript	n.242C>T		non_coding_transcript_exon_variant	1/2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

149846

Hom.:

Cov.:

FAILED QC

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000187

AC:

AN:

1067548

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

509102

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000291

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

149846

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73080

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Combined immunodeficiency due to ORAI1 deficiency;C4014557:Myopathy, tubular aggregate, 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 23, 2023

The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with ORAI1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1897344). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 3 of the ORAI1 protein (p.Pro3Leu). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.085

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.091

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.19

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.54

M_CAP

Pathogenic

0.92

MetaRNN

Benign

0.24

MetaSVM

Benign

-1.1

MutationTaster

Benign

0.98

PrimateAI

Pathogenic

0.91

Polyphen

0.0050

MutPred

0.23

Gain of catalytic residue at E4 (P = 0.0046);

ClinPred

0.96

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.14

gMVP

0.55

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over