chr12-121626524-C-A

Variant names:

• chr12-121626524-C-A
• rs7138600
• ENST00000698901.2:n.16C>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000698901.2(ORAI1):​n.16C>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0108 in 169,778 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (38 hom., cov: 30)
  • Exomes 𝑓: 0.0012 (1 hom.)
• Consequence: ORAI1 ENST00000698901.2 non_coding_transcript_exon
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.201
• Publications: 0 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

ENSG00000302371 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 12-121626524-C-A is Benign according to our data. Variant chr12-121626524-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1205576.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0119 (1815/151942) while in subpopulation AFR AF = 0.0418 (1735/41498). AF 95% confidence interval is 0.0402. There are 38 homozygotes in GnomAd4. There are 835 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 38 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000698901.2. 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.-6C>A		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORAI1	ENST00000698901.2		n.16C>A		non_coding_transcript_exon	Exon 1 of 2
	ENSG00000302371	ENST00000786201.1		n.179+380G>T		intron	N/A
	ENSG00000302371	ENST00000786202.1		n.181+380G>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1813 AN: 151836 Hom.: 38 Cov.: 30

Gnomad AFR AF: 0.0419

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.00672

GnomAD4 exome AF: 0.00123 AC: 22 AN: 17836 Hom.: 1 Cov.: 2 AF XY: 0.00120 AC XY: 12 AN XY: 9988

African (AFR) AF: 0.0497 AC: 18 AN: 362

American (AMR) AF: 0.00162 AC: 1 AN: 616

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 458

East Asian (EAS) AF: 0.00 AC: 0 AN: 592

South Asian (SAS) AF: 0.00 AC: 0 AN: 190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1930

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 88

European-Non Finnish (NFE) AF: 0.0000797 AC: 1 AN: 12550

Other (OTH) AF: 0.00190 AC: 2 AN: 1050

GnomAD4 genome AF: 0.0119 AC: 1815 AN: 151942 Hom.: 38 Cov.: 30 AF XY: 0.0112 AC XY: 835 AN XY: 74300

African (AFR) AF: 0.0418 AC: 1735 AN: 41498

American (AMR) AF: 0.00406 AC: 62 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10512

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000589 AC: 4 AN: 67894

Other (OTH) AF: 0.00665 AC: 14 AN: 2106

Alfa AF: 0.000425 Hom.: 1

Bravo AF: 0.0138

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	11
DANN	Benign	0.69
PhyloP100		-0.20
PromoterAI		-0.13	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs7138600; hg19: chr12-122064429;