12-121626748-T-C

Variant names:

• chr12-121626748-T-C
• rs1594204338
• ENST00000617316.2:c.6T>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The ENST00000617316.2(ORAI1):​c.6T>C​(p.His2His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000282 in 1,064,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: ORAI1 ENST00000617316.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.81
• 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: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 12-121626748-T-C is Benign according to our data. Variant chr12-121626748-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2938496.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.82 with no splicing effect.

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.219T>C		non_coding_transcript_exon	Exon 1 of 2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORAI1	ENST00000617316.2	TSL:1	c.6T>C	p.His2His	synonymous	Exon 1 of 3	ENSP00000482568.2	Q96D31-1
	ORAI1	ENST00000646827.1		n.199T>C		non_coding_transcript_exon	Exon 1 of 2
	ORAI1	ENST00000698901.2		n.240T>C		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000282 AC: 3 AN: 1064652 Hom.: 0 Cov.: 28 AF XY: 0.00000197 AC XY: 1 AN XY: 507722

African (AFR) AF: 0.00 AC: 0 AN: 21038

American (AMR) AF: 0.00 AC: 0 AN: 6814

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12002

East Asian (EAS) AF: 0.00 AC: 0 AN: 21628

South Asian (SAS) AF: 0.00 AC: 0 AN: 22208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28794

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2714

European-Non Finnish (NFE) AF: 0.00000330 AC: 3 AN: 908502

Other (OTH) AF: 0.00 AC: 0 AN: 40952

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Combined immunodeficiency due to ORAI1 deficiency;C4014557:Myopathy, tubular aggregate, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	13
DANN	Benign	0.77
PhyloP100		1.8
PromoterAI		-0.38	Neutral

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: rs1594204338; hg19: chr12-122064653;