chr12-121641442-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The ENST00000617316.2(ORAI1):c.705T>C(p.Ala235Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0138 in 1,613,930 control chromosomes in the GnomAD database, including 867 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.029 ( 177 hom., cov: 33)

Exomes 𝑓: 0.012 ( 690 hom. )

Consequence

ORAI1
ENST00000617316.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -3.48

Publications

9 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.96).

BP6

Variant 12-121641442-T-C is Benign according to our data. Variant chr12-121641442-T-C is described in ClinVar as Benign. ClinVar VariationId is 379437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.48 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ORAI1	NR_186857.1 link	n.923T>C		non_coding_transcript_exon_variant	Exon 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
ORAI1	ENST00000617316.2 link	c.705T>C	p.Ala235Ala	synonymous_variant	Exon 3 of 3	1	ENSP00000482568.2	Q96D31-1
ORAI1	ENST00000611718.1 link	n.761T>C		non_coding_transcript_exon_variant	Exon 2 of 2	5
ORAI1	ENST00000646827.1 link	n.903T>C		non_coding_transcript_exon_variant	Exon 2 of 2
ORAI1	ENST00000698901.2 link	n.827T>C		non_coding_transcript_exon_variant	Exon 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.0292

AC:

4442

AN:

152240

Hom.:

176

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0750

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.0120

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.111

Gnomad SAS

AF:

0.0107

Gnomad FIN

AF:

0.00499

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00594

Gnomad OTH

AF:

0.0225

GnomAD2 exomes

AF:

0.0165

AC:

4110

AN:

248770

AF XY:

0.0147

show subpopulations

Gnomad AFR exome

AF:

0.0765

Gnomad AMR exome

AF:

0.00637

Gnomad ASJ exome

AF:

0.00278

Gnomad EAS exome

AF:

0.0915

Gnomad FIN exome

AF:

0.00586

Gnomad NFE exome

AF:

0.00568

Gnomad OTH exome

AF:

0.0122

GnomAD4 exome

AF:

0.0122

AC:

17880

AN:

1461572

Hom.:

690

Cov.:

AF XY:

0.0119

AC XY:

8633

AN XY:

727122

show subpopulations

African (AFR)

AF:

0.0788

AC:

2638

AN:

33476

American (AMR)

AF:

0.00653

AC:

292

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00214

AC:

AN:

26132

East Asian (EAS)

AF:

0.149

AC:

5900

AN:

39700

South Asian (SAS)

AF:

0.00692

AC:

597

AN:

86258

European-Finnish (FIN)

AF:

0.00557

AC:

296

AN:

53142

Middle Eastern (MID)

AF:

0.00884

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00643

AC:

7145

AN:

1111990

Other (OTH)

AF:

0.0150

AC:

905

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

1240

2480

3720

4960

6200

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

384

768

1152

1536

1920

<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:

0.0292

AC:

4451

AN:

152358

Hom.:

177

Cov.:

AF XY:

0.0294

AC XY:

2191

AN XY:

74510

show subpopulations

African (AFR)

AF:

0.0749

AC:

3117

AN:

41588

American (AMR)

AF:

0.0120

AC:

184

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

3472

East Asian (EAS)

AF:

0.111

AC:

578

AN:

5186

South Asian (SAS)

AF:

0.0112

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00499

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00594

AC:

404

AN:

68028

Other (OTH)

AF:

0.0222

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

216

432

648

864

1080

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

192

240

<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:

0.0130

Hom.:

Bravo

AF:

0.0312

Asia WGS

AF:

0.0580

AC:

202

AN:

3478

EpiCase

AF:

0.00562

EpiControl

AF:

0.00551

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

May 13, 2016

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:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

-0.96

CADD

Benign

0.065

(source)

DANN

Benign

0.25

PhyloP100

-3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Mutation Taster

=99/1

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