rs1356450700

Variant names:

• chr12-121626764-C-G
• rs1356450700
• ENST00000617316.2:c.22C>G

Your query was ambiguous. Multiple possible variants found:

• chr12-121626764-C-G
• chr12-121626764-C-T

Variant summary

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

The ENST00000617316.2(ORAI1):​c.22C>G​(p.Pro8Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000391 in 1,253,410 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. P8S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: ORAI1 ENST00000617316.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.64
• Publications: 1 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=0.36548316).

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.235C>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.22C>G	p.Pro8Ala	missense	Exon 1 of 3	ENSP00000482568.2	Q96D31-1
	ORAI1	ENST00000646827.1		n.215C>G		non_coding_transcript_exon	Exon 1 of 2
	ORAI1	ENST00000698901.2		n.256C>G		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.0000266 AC: 4 AN: 150168 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: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000446

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000408 AC: 45 AN: 1103242 Hom.: 0 Cov.: 29 AF XY: 0.0000435 AC XY: 23 AN XY: 528474

African (AFR) AF: 0.00 AC: 0 AN: 21810

American (AMR) AF: 0.00 AC: 0 AN: 7468

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13030

East Asian (EAS) AF: 0.00 AC: 0 AN: 23540

South Asian (SAS) AF: 0.00 AC: 0 AN: 26400

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34504

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2868

European-Non Finnish (NFE) AF: 0.0000484 AC: 45 AN: 930446

Other (OTH) AF: 0.00 AC: 0 AN: 43176

GnomAD4 genome AF: 0.0000266 AC: 4 AN: 150168 Hom.: 0 Cov.: 30 AF XY: 0.0000273 AC XY: 2 AN XY: 73276

African (AFR) AF: 0.0000243 AC: 1 AN: 41208

American (AMR) AF: 0.00 AC: 0 AN: 15112

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3448

East Asian (EAS) AF: 0.00 AC: 0 AN: 5118

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9982

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000446 AC: 3 AN: 67202

Other (OTH) AF: 0.00 AC: 0 AN: 2054

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	0.058
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.41	T
M_CAP	Pathogenic	0.87	D
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.91	T
PhyloP100		1.6
PrimateAI	Pathogenic	0.87	D
Polyphen		0.88	P
MutPred		0.20		Loss of glycosylation at P8 (P = 0.0034)
ClinPred		0.99	D
GERP RS		3.9
PromoterAI		-0.30	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Varity_R		0.21
gMVP		0.60
Mutation Taster		=82/18	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: rs1356450700; hg19: chr12-122064669;