rs782531427

Variant names:

• chr12-121626857-C-A
• rs782531427
• ENST00000617316.2:c.115C>A

Your query was ambiguous. Multiple possible variants found:

• chr12-121626857-C-A
• chr12-121626857-C-G
• chr12-121626857-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000617316.2(ORAI1):​c.115C>A​(p.Pro39Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. P39L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ORAI1 ENST00000617316.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.22
• Publications: 2 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28519446).

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.328C>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.115C>A	p.Pro39Thr	missense	Exon 1 of 3	ENSP00000482568.2	Q96D31-1
	ORAI1	ENST00000611718.1	TSL:5	n.42C>A		non_coding_transcript_exon	Exon 1 of 2
	ORAI1	ENST00000646827.1		n.308C>A		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1398478 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 694566

African (AFR) AF: 0.00 AC: 0 AN: 28752

American (AMR) AF: 0.00 AC: 0 AN: 36892

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24272

East Asian (EAS) AF: 0.00 AC: 0 AN: 33522

South Asian (SAS) AF: 0.00 AC: 0 AN: 79438

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49754

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5232

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1083374

Other (OTH) AF: 0.00 AC: 0 AN: 57242

GnomAD4 genome Cov.: 27

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	0.064
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.079	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.41	T
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.29	T
PhyloP100		1.2
PrimateAI	Pathogenic	0.86	D
Polyphen		0.25	B
MutPred		0.21		Gain of catalytic residue at P43 (P = 5e-04)
ClinPred		0.87	D
GERP RS		3.8
PromoterAI		0.013	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.16
gMVP		0.57
Mutation Taster		=76/24	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: rs782531427; hg19: chr12-122064762;