12-121641283-C-T

Position:

• chr12-121641283-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The ENST00000617316.2(ORAI1):​c.546C>T​(p.Ile182=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: -0.831

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	Protein	UniProt
ORAI1	NM_032790.3	c.549C>T	p.Ile183=	synonymous_variant	3/3		NP_116179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ORAI1	ENST00000617316.2	c.546C>T	p.Ile182=	synonymous_variant	3/3	1		ENSP00000482568	P1
ORAI1	ENST00000611718.1	n.602C>T		non_coding_transcript_exon_variant	2/2	5
ORAI1	ENST00000646827.1	n.744C>T		non_coding_transcript_exon_variant	2/2
ORAI1	ENST00000698901.1	n.668C>T		non_coding_transcript_exon_variant	2/2

Frequencies

GnomAD3 genomes AF: 0.156 AC: 23739 AN: 152110 Hom.: 2209 Cov.: 33

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

GnomAD3 exomes AF: 0.203 AC: 50725 AN: 249926 Hom.: 5920 AF XY: 0.207 AC XY: 28030 AN XY: 135214

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 SAS exome AF: 0.332

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.: 34 AF XY: 0.183 AC XY: 132880 AN XY: 727222

Gnomad4 AFR exome AF: 0.0871

Gnomad4 AMR exome AF: 0.294

Gnomad4 ASJ exome AF: 0.201

Gnomad4 EAS exome AF: 0.240

Gnomad4 SAS exome AF: 0.331

Gnomad4 FIN exome AF: 0.123

Gnomad4 NFE exome AF: 0.163

Gnomad4 OTH exome AF: 0.189

GnomAD4 genome AF: 0.156 AC: 23783 AN: 152226 Hom.: 2215 Cov.: 33 AF XY: 0.161 AC XY: 11948 AN XY: 74432

Gnomad4 AFR AF: 0.0871

Gnomad4 AMR AF: 0.242

Gnomad4 ASJ AF: 0.214

Gnomad4 EAS AF: 0.253

Gnomad4 SAS AF: 0.326

Gnomad4 FIN AF: 0.118

Gnomad4 NFE AF: 0.160

Gnomad4 OTH AF: 0.181

Alfa AF: 0.174 Hom.: 3557

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:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 20, 2015	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. -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	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. -

not provided Benign:1 Other:1

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	3.4
DANN	Benign	0.79

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

LitVar

Other links and lift over

dbSNP: rs3741595; hg19: chr12-122079189; COSMIC: COSV57491137;