12-121638011-T-C

Variant names:

• chr12-121638011-T-C
• rs6486795
• ENST00000617316.2:c.304-3030T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000617316.2(ORAI1):​c.304-3030T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 152,200 control chromosomes in the GnomAD database, including 5,698 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.26 (5698 hom., cov: 32)
• Consequence: ORAI1 ENST00000617316.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.61
• Publications: 28 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.385 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.522-3030T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORAI1	ENST00000617316.2	TSL:1	c.304-3030T>C		intron	N/A	ENSP00000482568.2	Q96D31-1
	ORAI1	ENST00000611718.1	TSL:5	n.360-3030T>C		intron	N/A
	ORAI1	ENST00000646827.1		n.502-3030T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.260 AC: 39600 AN: 152082 Hom.: 5678 Cov.: 32

Gnomad AFR AF: 0.335

Gnomad AMI AF: 0.265

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.253

Gnomad EAS AF: 0.399

Gnomad SAS AF: 0.378

Gnomad FIN AF: 0.152

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.206

Gnomad OTH AF: 0.253

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.261 AC: 39686 AN: 152200 Hom.: 5698 Cov.: 32 AF XY: 0.264 AC XY: 19635 AN XY: 74410

African (AFR) AF: 0.336 AC: 13945 AN: 41522

American (AMR) AF: 0.294 AC: 4499 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.253 AC: 877 AN: 3470

East Asian (EAS) AF: 0.399 AC: 2065 AN: 5170

South Asian (SAS) AF: 0.379 AC: 1828 AN: 4826

European-Finnish (FIN) AF: 0.152 AC: 1614 AN: 10608

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.206 AC: 13991 AN: 68004

Other (OTH) AF: 0.256 AC: 541 AN: 2116

Alfa AF: 0.234 Hom.: 2517

Bravo AF: 0.272

Asia WGS AF: 0.414 AC: 1437 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.091
DANN	Benign	0.41
PhyloP100		-1.6
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs6486795;

hg19: chr12-122075917;