12-121641776-AT-ATT

Variant names:

• chr12-121641776-A-AT
• rs35558190
• ENST00000617316.2:c.*138dupT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The ENST00000617316.2(ORAI1):​c.*138dupT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 1,123,738 control chromosomes in the GnomAD database, including 19,793 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.16 (2320 hom., cov: 29)
  • Exomes 𝑓: 0.17 (17473 hom.)
• Consequence: ORAI1 ENST00000617316.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.33
• Publications: 5 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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.315 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.1262dupT		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.*138dupT		3_prime_UTR	Exon 3 of 3	ENSP00000482568.2	Q96D31-1
	ORAI1	ENST00000646827.1		n.1242dupT		non_coding_transcript_exon	Exon 2 of 2
	ORAI1	ENST00000698901.2		n.1166dupT		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.160 AC: 24282 AN: 152106 Hom.: 2314 Cov.: 29

Gnomad AFR AF: 0.0878

Gnomad AMI AF: 0.258

Gnomad AMR AF: 0.244

Gnomad ASJ AF: 0.220

Gnomad EAS AF: 0.253

Gnomad SAS AF: 0.329

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.166

Gnomad OTH AF: 0.183

GnomAD4 exome AF: 0.173 AC: 168415 AN: 971514 Hom.: 17473 Cov.: 13 AF XY: 0.180 AC XY: 89211 AN XY: 496116

African (AFR) AF: 0.0814 AC: 1891 AN: 23242

American (AMR) AF: 0.275 AC: 8924 AN: 32496

Ashkenazi Jewish (ASJ) AF: 0.198 AC: 4226 AN: 21346

East Asian (EAS) AF: 0.234 AC: 8440 AN: 35998

South Asian (SAS) AF: 0.323 AC: 23075 AN: 71474

European-Finnish (FIN) AF: 0.124 AC: 4437 AN: 35762

Middle Eastern (MID) AF: 0.250 AC: 790 AN: 3156

European-Non Finnish (NFE) AF: 0.154 AC: 108669 AN: 704366

Other (OTH) AF: 0.182 AC: 7963 AN: 43674

GnomAD4 genome AF: 0.160 AC: 24327 AN: 152224 Hom.: 2320 Cov.: 29 AF XY: 0.164 AC XY: 12191 AN XY: 74412

African (AFR) AF: 0.0882 AC: 3664 AN: 41560

American (AMR) AF: 0.245 AC: 3744 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.220 AC: 763 AN: 3470

East Asian (EAS) AF: 0.253 AC: 1308 AN: 5172

South Asian (SAS) AF: 0.328 AC: 1585 AN: 4826

European-Finnish (FIN) AF: 0.119 AC: 1260 AN: 10604

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.166 AC: 11306 AN: 68004

Other (OTH) AF: 0.185 AC: 392 AN: 2114

Alfa AF: 0.155 Hom.: 213

Bravo AF: 0.164

Asia WGS AF: 0.312 AC: 1085 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
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: rs35558190; hg19: chr12-122079682; COSMIC: COSV57492478; COSMIC: COSV57492478;