ENST00000617316.2:c.13C>G

Variant names:

• chr12-121626755-C-G
• rs1253665950
• ENST00000617316.2:c.13C>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The ENST00000617316.2(ORAI1):​c.13C>G​(p.Pro5Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000057 in 1,227,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict 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. P5L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000019 (0 hom.)
• Consequence: ORAI1 ENST00000617316.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.35
• 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 -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15803477).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000333 (5/150190) while in subpopulation EAS AF = 0.000784 (4/5100). AF 95% confidence interval is 0.000268. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.226C>G		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.13C>G	p.Pro5Ala	missense	Exon 1 of 3	ENSP00000482568.2	Q96D31-1
	ORAI1	ENST00000646827.1		n.206C>G		non_coding_transcript_exon	Exon 1 of 2
	ORAI1	ENST00000698901.2		n.247C>G		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.0000333 AC: 5 AN: 150082 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000782

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000186 AC: 2 AN: 1077206 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 514114

African (AFR) AF: 0.00 AC: 0 AN: 21310

American (AMR) AF: 0.00 AC: 0 AN: 7028

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12356

East Asian (EAS) AF: 0.0000892 AC: 2 AN: 22426

South Asian (SAS) AF: 0.00 AC: 0 AN: 23038

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31146

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 915488

Other (OTH) AF: 0.00 AC: 0 AN: 41656

GnomAD4 genome AF: 0.0000333 AC: 5 AN: 150190 Hom.: 0 Cov.: 30 AF XY: 0.0000545 AC XY: 4 AN XY: 73340

African (AFR) AF: 0.0000242 AC: 1 AN: 41304

American (AMR) AF: 0.00 AC: 0 AN: 15118

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3446

East Asian (EAS) AF: 0.000784 AC: 4 AN: 5100

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9920

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67196

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

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	0.059
BayesDel_addAF	Benign	-0.0035	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.40	T
M_CAP	Pathogenic	0.91	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.98	T
PhyloP100		1.4
PrimateAI	Pathogenic	0.88	D
Polyphen		0.0	B
MutPred		0.18		Gain of catalytic residue at P7 (P = 0.0143)
ClinPred		0.27	T
GERP RS		3.0
PromoterAI		0.13	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.13
gMVP		0.49
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: rs1253665950; hg19: chr12-122064660;