ENST00000617316.2:c.546C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The ENST00000617316.2(ORAI1):c.546C>T(p.Ile182Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.176 in 1,614,070 control chromosomes in the GnomAD database, including 27,597 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.16 ( 2215 hom., cov: 33)

Exomes 𝑓: 0.18 ( 25382 hom. )

Consequence

ORAI1
ENST00000617316.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4O:1

Conservation

PhyloP100: -0.831

Publications

43 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: Orphanet, Labcorp Genetics (formerly Invitae)
Stormorken syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ORAI1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.42).

BP6

Variant 12-121641283-C-T is Benign according to our data. Variant chr12-121641283-C-T is described in ClinVar as Benign. ClinVar VariationId is 379393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.831 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.313 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ORAI1	NR_186857.1 link	n.764C>T		non_coding_transcript_exon_variant	Exon 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein
ORAI1	ENST00000617316.2 link	c.546C>T	p.Ile182Ile	synonymous_variant	Exon 3 of 3	1	ENSP00000482568.2
ORAI1	ENST00000611718.1 link	n.602C>T		non_coding_transcript_exon_variant	Exon 2 of 2	5
ORAI1	ENST00000646827.1 link	n.744C>T		non_coding_transcript_exon_variant	Exon 2 of 2
ORAI1	ENST00000698901.2 link	n.668C>T		non_coding_transcript_exon_variant	Exon 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.156

AC:

23739

AN:

152110

Hom.:

2209

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0868

Gnomad AMI

AF:

0.259

Gnomad AMR

AF:

0.241

Gnomad ASJ

AF:

0.214

Gnomad EAS

AF:

0.253

Gnomad SAS

AF:

0.327

Gnomad FIN

AF:

0.118

Gnomad MID

AF:

0.234

Gnomad NFE

AF:

0.160

Gnomad OTH

AF:

0.178

GnomAD2 exomes

AF:

0.203

AC:

50725

AN:

249926

AF XY:

0.207

show subpopulations

Gnomad AFR exome

AF:

0.0842

Gnomad AMR exome

AF:

0.300

Gnomad ASJ exome

AF:

0.198

Gnomad EAS exome

AF:

0.258

Gnomad FIN exome

AF:

0.119

Gnomad NFE exome

AF:

0.163

Gnomad OTH exome

AF:

0.188

GnomAD4 exome

AF:

0.178

AC:

260437

AN:

1461844

Hom.:

25382

Cov.:

AF XY:

0.183

AC XY:

132880

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.0871

AC:

2915

AN:

33480

American (AMR)

AF:

0.294

AC:

13150

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.201

AC:

5244

AN:

26136

East Asian (EAS)

AF:

0.240

AC:

9512

AN:

39700

South Asian (SAS)

AF:

0.331

AC:

28538

AN:

86258

European-Finnish (FIN)

AF:

0.123

AC:

6564

AN:

53406

Middle Eastern (MID)

AF:

0.270

AC:

1557

AN:

5768

European-Non Finnish (NFE)

AF:

0.163

AC:

181535

AN:

1111988

Other (OTH)

AF:

0.189

AC:

11422

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

15835

31670

47504

63339

79174

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6672

13344

20016

26688

33360

<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

AF:

0.156

AC:

23783

AN:

152226

Hom.:

2215

Cov.:

AF XY:

0.161

AC XY:

11948

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.0871

AC:

3618

AN:

41548

American (AMR)

AF:

0.242

AC:

3701

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.214

AC:

743

AN:

3472

East Asian (EAS)

AF:

0.253

AC:

1310

AN:

5168

South Asian (SAS)

AF:

0.326

AC:

1574

AN:

4824

European-Finnish (FIN)

AF:

0.118

AC:

1250

AN:

10600

Middle Eastern (MID)

AF:

0.238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.160

AC:

10899

AN:

67998

Other (OTH)

AF:

0.181

AC:

383

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1053

2105

3158

4210

5263

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

280

560

840

1120

1400

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.171

Hom.:

4338

Bravo

AF:

0.161

Asia WGS

AF:

0.311

AC:

1081

AN:

3478

EpiCase

AF:

0.177

EpiControl

AF:

0.174

ClinVar

Significance: Benign

Submissions summary: Benign:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 51% of patients studied by a panel of primary immunodeficiencies. Number of patients: 48. Only high quality variants are reported.

Oct 20, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

not provided

Benign:1Other:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing.

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

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.42

CADD

Benign

3.4

(source)

DANN

Benign

0.79

PhyloP100

-0.83

Mutation Taster

=98/2

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over