12-121641762-A-G

Variant names:

• chr12-121641762-A-G
• rs712853
• ENST00000617316.2:c.*119A>G

Variant summary

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

The ENST00000617316.2(ORAI1):​c.*119A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.265 in 1,321,178 control chromosomes in the GnomAD database, including 51,898 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 0.35 (10925 hom., cov: 34)
  • Exomes 𝑓: 0.25 (40973 hom.)
• Consequence: ORAI1 ENST00000617316.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.696
• Publications: 29 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.585 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ORAI1	NR_186857.1	n.1243A>G		non_coding_transcript_exon_variant	Exon 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ORAI1	ENST00000617316.2	c.*119A>G		3_prime_UTR_variant	Exon 3 of 3	1		ENSP00000482568.2
ORAI1	ENST00000646827.1	n.1223A>G		non_coding_transcript_exon_variant	Exon 2 of 2
ORAI1	ENST00000698901.2	n.1147A>G		non_coding_transcript_exon_variant	Exon 2 of 2
ORAI1	ENST00000611718.1	n.*229A>G		downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.348 AC: 52311 AN: 150270 Hom.: 10897 Cov.: 34

Gnomad AFR AF: 0.591

Gnomad AMI AF: 0.154

Gnomad AMR AF: 0.232

Gnomad ASJ AF: 0.159

Gnomad EAS AF: 0.342

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.307

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.257

Gnomad OTH AF: 0.283

GnomAD4 exome AF: 0.254 AC: 297738 AN: 1170790 Hom.: 40973 Cov.: 16 AF XY: 0.251 AC XY: 148418 AN XY: 591646

African (AFR) AF: 0.596 AC: 16365 AN: 27478

American (AMR) AF: 0.190 AC: 7720 AN: 40610

Ashkenazi Jewish (ASJ) AF: 0.160 AC: 3809 AN: 23816

East Asian (EAS) AF: 0.368 AC: 13975 AN: 37948

South Asian (SAS) AF: 0.178 AC: 14167 AN: 79542

European-Finnish (FIN) AF: 0.297 AC: 11141 AN: 37488

Middle Eastern (MID) AF: 0.152 AC: 595 AN: 3922

European-Non Finnish (NFE) AF: 0.250 AC: 217503 AN: 869284

Other (OTH) AF: 0.246 AC: 12463 AN: 50702

GnomAD4 genome AF: 0.348 AC: 52387 AN: 150388 Hom.: 10925 Cov.: 34 AF XY: 0.345 AC XY: 25306 AN XY: 73398

African (AFR) AF: 0.591 AC: 24452 AN: 41388

American (AMR) AF: 0.232 AC: 3433 AN: 14800

Ashkenazi Jewish (ASJ) AF: 0.159 AC: 545 AN: 3428

East Asian (EAS) AF: 0.343 AC: 1744 AN: 5090

South Asian (SAS) AF: 0.199 AC: 904 AN: 4544

European-Finnish (FIN) AF: 0.307 AC: 3230 AN: 10524

Middle Eastern (MID) AF: 0.139 AC: 40 AN: 288

European-Non Finnish (NFE) AF: 0.257 AC: 17323 AN: 67382

Other (OTH) AF: 0.281 AC: 581 AN: 2070

Alfa AF: 0.296 Hom.: 11355

Bravo AF: 0.349

Asia WGS AF: 0.266 AC: 928 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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.2
DANN	Benign	0.69
PhyloP100		0.70
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: rs712853; hg19: chr12-122079668; COSMIC: COSV57491929; COSMIC: COSV57491929;