12-121626750-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000617316.2(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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P3Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000019 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ORAI1
ENST00000617316.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.34

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

tubular aggregate myopathy
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
myopathy, tubular aggregate, 2
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
combined immunodeficiency due to ORAI1 deficiency
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
Stormorken syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ORAI1 links:

ENSG00000302371 (HGNC:):

ENSG00000302371 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.23516801).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000617316.2. 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
	ORAI1	NR_186857.1		n.221C>T		non_coding_transcript_exon	Exon 1 of 2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ORAI1	ENST00000617316.2	TSL:1	c.8C>T	p.Pro3Leu	missense	Exon 1 of 3	ENSP00000482568.2	Q96D31-1
ORAI1	ENST00000646827.1		n.201C>T		non_coding_transcript_exon	Exon 1 of 2
ORAI1	ENST00000698901.2		n.242C>T		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

149846

Hom.:

Cov.:

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

African (AFR)

AF:

0.00

AC:

AN:

21106

American (AMR)

AF:

0.000291

AC:

AN:

6870

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12102

East Asian (EAS)

AF:

0.00

AC:

AN:

21838

South Asian (SAS)

AF:

0.00

AC:

AN:

22256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29510

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2726

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

910020

Other (OTH)

AF:

0.00

AC:

AN:

41120

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

African (AFR)

AF:

0.00

AC:

AN:

41186

American (AMR)

AF:

0.00

AC:

AN:

15086

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3438

East Asian (EAS)

AF:

0.00

AC:

AN:

5114

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9912

Middle Eastern (MID)

AF:

0.00

AC:

AN:

308

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67006

Other (OTH)

AF:

0.00

AC:

AN:

2058

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Combined immunodeficiency due to ORAI1 deficiency;C4014557:Myopathy, tubular aggregate, 2 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.085

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

(source)

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

PhyloP100

2.3

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

PromoterAI

-0.37

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.14

gMVP

0.55

Mutation Taster

=96/4

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over