rs3825174

Variant names:

• chr12-121641523-T-C
• rs3825174
• ENST00000617316.2:c.786T>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.786T>C​(p.Val262Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0139 in 1,613,696 control chromosomes in the GnomAD database, including 872 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (178 hom., cov: 33)
  • Exomes 𝑓: 0.012 (694 hom.)
• Consequence: ORAI1 ENST00000617316.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.14
• 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=-0.53).
• BP6: Variant 12-121641523-T-C is Benign according to our data. Variant chr12-121641523-T-C is described in ClinVar as Benign. ClinVar VariationId is 379438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.14 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.1004T>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.786T>C	p.Val262Val	synonymous	Exon 3 of 3	ENSP00000482568.2	Q96D31-1
	ORAI1	ENST00000611718.1	TSL:5	n.842T>C		non_coding_transcript_exon	Exon 2 of 2
	ORAI1	ENST00000646827.1		n.984T>C		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.0296 AC: 4506 AN: 152202 Hom.: 177 Cov.: 33

Gnomad AFR AF: 0.0765

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0122

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.112

Gnomad SAS AF: 0.0103

Gnomad FIN AF: 0.00499

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00594

Gnomad OTH AF: 0.0234

GnomAD2 exomes AF: 0.0166 AC: 4136 AN: 248536 AF XY: 0.0148

Gnomad AFR exome AF: 0.0779

Gnomad AMR exome AF: 0.00655

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.0916

Gnomad FIN exome AF: 0.00590

Gnomad NFE exome AF: 0.00567

Gnomad OTH exome AF: 0.0124

GnomAD4 exome AF: 0.0123 AC: 17959 AN: 1461376 Hom.: 694 Cov.: 34 AF XY: 0.0119 AC XY: 8670 AN XY: 727036

African (AFR) AF: 0.0802 AC: 2686 AN: 33476

American (AMR) AF: 0.00666 AC: 298 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00214 AC: 56 AN: 26136

East Asian (EAS) AF: 0.149 AC: 5899 AN: 39698

South Asian (SAS) AF: 0.00694 AC: 599 AN: 86258

European-Finnish (FIN) AF: 0.00557 AC: 295 AN: 52918

Middle Eastern (MID) AF: 0.00902 AC: 52 AN: 5768

European-Non Finnish (NFE) AF: 0.00643 AC: 7149 AN: 1112006

Other (OTH) AF: 0.0153 AC: 925 AN: 60392

GnomAD4 genome AF: 0.0296 AC: 4515 AN: 152320 Hom.: 178 Cov.: 33 AF XY: 0.0297 AC XY: 2210 AN XY: 74484

African (AFR) AF: 0.0764 AC: 3178 AN: 41578

American (AMR) AF: 0.0122 AC: 187 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.112 AC: 578 AN: 5174

South Asian (SAS) AF: 0.0108 AC: 52 AN: 4830

European-Finnish (FIN) AF: 0.00499 AC: 53 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00594 AC: 404 AN: 68030

Other (OTH) AF: 0.0232 AC: 49 AN: 2116

Alfa AF: 0.0133 Hom.: 38

Bravo AF: 0.0318

Asia WGS AF: 0.0580 AC: 202 AN: 3478

EpiCase AF: 0.00562

EpiControl AF: 0.00551

ClinVar

ClinVar submissions

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	-0.53
CADD	Benign	11
DANN	Benign	0.65
PhyloP100		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=91/9	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: rs3825174; hg19: chr12-122079429;