rs3741597

Variant names:

• chr12-121641442-T-C
• rs3741597
• ENST00000617316.2:c.705T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.48
• Publications: 9 publications found

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

ACMG classification

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.

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.923T>C		non_coding_transcript_exon	Exon 2 of 2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORAI1	ENST00000617316.2	TSL:1	c.705T>C	p.Ala235Ala	synonymous	Exon 3 of 3	ENSP00000482568.2
	ORAI1	ENST00000611718.1	TSL:5	n.761T>C		non_coding_transcript_exon	Exon 2 of 2
	ORAI1	ENST00000646827.1		n.903T>C		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.0292 AC: 4442 AN: 152240 Hom.: 176 Cov.: 33

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

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.: 34 AF XY: 0.0119 AC XY: 8633 AN XY: 727122

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: 56 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: 51 AN: 5768

European-Non Finnish (NFE) AF: 0.00643 AC: 7145 AN: 1111990

Other (OTH) AF: 0.0150 AC: 905 AN: 60382

GnomAD4 genome AF: 0.0292 AC: 4451 AN: 152358 Hom.: 177 Cov.: 33 AF XY: 0.0294 AC XY: 2191 AN XY: 74510

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: 8 AN: 3472

East Asian (EAS) AF: 0.111 AC: 578 AN: 5186

South Asian (SAS) AF: 0.0112 AC: 54 AN: 4834

European-Finnish (FIN) AF: 0.00499 AC: 53 AN: 10630

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00594 AC: 404 AN: 68028

Other (OTH) AF: 0.0222 AC: 47 AN: 2114

Alfa AF: 0.0130 Hom.: 67

Bravo AF: 0.0312

Asia WGS AF: 0.0580 AC: 202 AN: 3478

EpiCase AF: 0.00562

EpiControl AF: 0.00551

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Combined immunodeficiency due to ORAI1 deficiency;C4014557:Myopathy, tubular aggregate, 2 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.065
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)

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

Other links and lift over

dbSNP: rs3741597; hg19: chr12-122079348; COSMIC: COSV57492155;