Genetic Variant ENST00000617316.2:c.798T>C (chr12-121641535-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

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

The ENST00000617316.2(ORAI1):c.798T>C(p.Thr266Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.446 in 1,613,108 control chromosomes in the GnomAD database, including 164,867 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.51 ( 20788 hom., cov: 33)

Exomes 𝑓: 0.44 ( 144079 hom. )

Consequence

ORAI1
ENST00000617316.2 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.776

Publications

33 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:

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=-0.74).

BP6

Variant 12-121641535-T-C is Benign according to our data. Variant chr12-121641535-T-C is described in ClinVar as Benign. ClinVar VariationId is 379394.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.776 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.681 is higher than 0.05.

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.1016T>C		non_coding_transcript_exon	Exon 2 of 2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ORAI1	ENST00000617316.2	TSL:1	c.798T>C	p.Thr266Thr	synonymous	Exon 3 of 3	ENSP00000482568.2	Q96D31-1
ORAI1	ENST00000646827.1		n.996T>C		non_coding_transcript_exon	Exon 2 of 2
ORAI1	ENST00000698901.2		n.920T>C		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.507

AC:

77088

AN:

152052

Hom.:

20732

Cov.:

show subpopulations

Gnomad AFR

AF:

0.687

Gnomad AMI

AF:

0.407

Gnomad AMR

AF:

0.472

Gnomad ASJ

AF:

0.377

Gnomad EAS

AF:

0.593

Gnomad SAS

AF:

0.515

Gnomad FIN

AF:

0.423

Gnomad MID

AF:

0.377

Gnomad NFE

AF:

0.421

Gnomad OTH

AF:

0.462

GnomAD2 exomes

AF:

0.469

AC:

116387

AN:

248184

AF XY:

0.466

show subpopulations

Gnomad AFR exome

AF:

0.693

Gnomad AMR exome

AF:

0.488

Gnomad ASJ exome

AF:

0.366

Gnomad EAS exome

AF:

0.596

Gnomad FIN exome

AF:

0.417

Gnomad NFE exome

AF:

0.423

Gnomad OTH exome

AF:

0.421

GnomAD4 exome

AF:

0.440

AC:

642210

AN:

1460938

Hom.:

144079

Cov.:

AF XY:

0.441

AC XY:

320366

AN XY:

726846

show subpopulations

African (AFR)

AF:

0.699

AC:

23390

AN:

33478

American (AMR)

AF:

0.487

AC:

21759

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.367

AC:

9587

AN:

26132

East Asian (EAS)

AF:

0.610

AC:

24209

AN:

39700

South Asian (SAS)

AF:

0.511

AC:

44045

AN:

86258

European-Finnish (FIN)

AF:

0.421

AC:

22093

AN:

52500

Middle Eastern (MID)

AF:

0.435

AC:

2507

AN:

5768

European-Non Finnish (NFE)

AF:

0.421

AC:

467982

AN:

1111988

Other (OTH)

AF:

0.441

AC:

26638

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

25311

50622

75934

101245

126556

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14532

29064

43596

58128

72660

<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:

0.507

AC:

77215

AN:

152170

Hom.:

20788

Cov.:

AF XY:

0.507

AC XY:

37740

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.688

AC:

28559

AN:

41532

American (AMR)

AF:

0.473

AC:

7224

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.377

AC:

1306

AN:

3468

East Asian (EAS)

AF:

0.594

AC:

3064

AN:

5156

South Asian (SAS)

AF:

0.515

AC:

2489

AN:

4830

European-Finnish (FIN)

AF:

0.423

AC:

4486

AN:

10600

Middle Eastern (MID)

AF:

0.374

AC:

110

AN:

294

European-Non Finnish (NFE)

AF:

0.421

AC:

28635

AN:

67988

Other (OTH)

AF:

0.462

AC:

972

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1928

3857

5785

7714

9642

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

684

1368

2052

2736

3420

<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:

0.458

Hom.:

9327

Bravo

AF:

0.517

Asia WGS

AF:

0.580

AC:

2020

AN:

3478

EpiCase

AF:

0.407

EpiControl

AF:

0.411

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

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

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

4.4

(source)

DANN

Benign

0.30

PhyloP100

-0.78

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over