rs1892783967

Variant names:

• chr12-121626750-C-A
• rs1892783967
• ENST00000617316.2:c.8C>A

Your query was ambiguous. Multiple possible variants found:

• chr12-121626750-C-A
• chr12-121626750-C-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The ENST00000617316.2(ORAI1):​c.8C>A​(p.Pro3Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000749 in 1,067,548 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P3L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: ORAI1 ENST00000617316.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.34
• 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 -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.33050177).

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.221C>A		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.8C>A	p.Pro3Gln	missense	Exon 1 of 3	ENSP00000482568.2	Q96D31-1
	ORAI1	ENST00000646827.1		n.201C>A		non_coding_transcript_exon	Exon 1 of 2
	ORAI1	ENST00000698901.2		n.242C>A		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000749 AC: 8 AN: 1067548 Hom.: 0 Cov.: 29 AF XY: 0.00000786 AC XY: 4 AN XY: 509102

African (AFR) AF: 0.00 AC: 0 AN: 21106

American (AMR) AF: 0.00 AC: 0 AN: 6870

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12102

East Asian (EAS) AF: 0.00 AC: 0 AN: 21838

South Asian (SAS) AF: 0.00 AC: 0 AN: 22256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29510

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2726

European-Non Finnish (NFE) AF: 0.00000879 AC: 8 AN: 910020

Other (OTH) AF: 0.00 AC: 0 AN: 41120

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

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
AlphaMissense	Benign	0.092
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.091	T
Eigen	Benign	0.071
Eigen_PC	Benign	0.065
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.42	T
M_CAP	Pathogenic	0.88	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-1.1	T
PhyloP100		2.3
PrimateAI	Pathogenic	0.88	D
Polyphen		0.93	P
MutPred		0.20		Gain of catalytic residue at P7 (P = 0.0078)
ClinPred		0.97	D
GERP RS		3.0
PromoterAI		-0.20	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.12
gMVP		0.55
Mutation Taster		=98/2	polymorphism

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: rs1892783967; hg19: chr12-122064655;