Genetic Variant ENST00000617316.2:c.115C>G (chr12-121626857-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The ENST00000617316.2(ORAI1):c.115C>G(p.Pro39Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000215 in 1,398,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/17 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. P39L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 27)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ORAI1
ENST00000617316.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.22

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:

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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=0.25277525).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ORAI1	NR_186857.1 link	n.328C>G		non_coding_transcript_exon_variant	Exon 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
ORAI1	ENST00000617316.2 link	c.115C>G	p.Pro39Ala	missense_variant	Exon 1 of 3	1	ENSP00000482568.2	Q96D31-1
ORAI1	ENST00000611718.1 link	n.42C>G		non_coding_transcript_exon_variant	Exon 1 of 2	5
ORAI1	ENST00000646827.1 link	n.308C>G		non_coding_transcript_exon_variant	Exon 1 of 2
ORAI1	ENST00000698901.1 link	n.349C>G		non_coding_transcript_exon_variant	Exon 1 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000215

AC:

AN:

1398482

Hom.:

Cov.:

AF XY:

0.00000288

AC XY:

AN XY:

694570

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000277

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000161

AC:

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

Feb 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 39 of the ORAI1 protein (p.Pro39Ala). This variant is not present in population databases (gnomAD no frequency). 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: 541940). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ORAI1 function (PMID: 19182790). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.073

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.81

DEOGEN2

Benign

0.11

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.42

M_CAP

Pathogenic

0.94

MetaRNN

Benign

0.25

MetaSVM

Benign

-0.43

PrimateAI

Pathogenic

0.86

Polyphen

0.25

MutPred

0.18

Gain of catalytic residue at P43 (P = 5e-04);

ClinPred

0.42

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.12

gMVP

0.47

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