12-121641729-C-T

Variant names:

• chr12-121641729-C-T
• rs76753792
• ENST00000617316.2:c.*86C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000617316.2(ORAI1):​c.*86C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 1,568,886 control chromosomes in the GnomAD database, including 866 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (181 hom., cov: 34)
  • Exomes 𝑓: 0.012 (685 hom.)
• Consequence: ORAI1 ENST00000617316.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.19
• Publications: 3 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: Orphanet, Labcorp Genetics (formerly Invitae)
• Stormorken syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 12-121641729-C-T is Benign according to our data. Variant chr12-121641729-C-T is described in ClinVar as Benign. ClinVar VariationId is 1243493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORAI1	NR_186857.1		n.1210C>T		non_coding_transcript_exon	Exon 2 of 2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORAI1	ENST00000617316.2	TSL:1	c.*86C>T		3_prime_UTR	Exon 3 of 3	ENSP00000482568.2
	ORAI1	ENST00000646827.1		n.1190C>T		non_coding_transcript_exon	Exon 2 of 2
	ORAI1	ENST00000698901.2		n.1114C>T		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.0296 AC: 4508 AN: 152234 Hom.: 180 Cov.: 34

Gnomad AFR AF: 0.0763

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0122

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.111

Gnomad SAS AF: 0.0116

Gnomad FIN AF: 0.00499

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00595

Gnomad OTH AF: 0.0234

GnomAD4 exome AF: 0.0124 AC: 17625 AN: 1416534 Hom.: 685 Cov.: 27 AF XY: 0.0121 AC XY: 8557 AN XY: 706516

African (AFR) AF: 0.0796 AC: 2611 AN: 32810

American (AMR) AF: 0.00664 AC: 296 AN: 44580

Ashkenazi Jewish (ASJ) AF: 0.00220 AC: 57 AN: 25876

East Asian (EAS) AF: 0.149 AC: 5874 AN: 39492

South Asian (SAS) AF: 0.00776 AC: 663 AN: 85446

European-Finnish (FIN) AF: 0.00524 AC: 204 AN: 38898

Middle Eastern (MID) AF: 0.00869 AC: 43 AN: 4946

European-Non Finnish (NFE) AF: 0.00642 AC: 6969 AN: 1085336

Other (OTH) AF: 0.0154 AC: 908 AN: 59150

GnomAD4 genome AF: 0.0296 AC: 4517 AN: 152352 Hom.: 181 Cov.: 34 AF XY: 0.0297 AC XY: 2213 AN XY: 74504

African (AFR) AF: 0.0763 AC: 3174 AN: 41590

American (AMR) AF: 0.0122 AC: 187 AN: 15308

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

East Asian (EAS) AF: 0.111 AC: 577 AN: 5182

South Asian (SAS) AF: 0.0120 AC: 58 AN: 4832

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: 0.00595 AC: 405 AN: 68026

Other (OTH) AF: 0.0232 AC: 49 AN: 2114

Alfa AF: 0.0193 Hom.: 15

Bravo AF: 0.0317

Asia WGS AF: 0.0580 AC: 202 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jul 07, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.17
DANN	Benign	0.61
PhyloP100		-3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs76753792; hg19: chr12-122079635; COSMIC: COSV57492505; COSMIC: COSV57492505;