rs3741596

Positions:

• chr12-121641389-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000617316.2(ORAI1):​c.652A>G​(p.Ser218Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0139 in 1,613,834 control chromosomes in the GnomAD database, including 875 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (181 hom., cov: 33)
  • Exomes 𝑓: 0.012 (694 hom.)
• Consequence: ORAI1 ENST00000617316.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.198

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020967424).
• BP6: Variant 12-121641389-A-G is Benign according to our data. Variant chr12-121641389-A-G is described in ClinVar as [Benign]. Clinvar id is 379436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ORAI1	NR_186857.1	n.870A>G		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ORAI1	ENST00000617316.2	c.652A>G	p.Ser218Gly	missense_variant	3/3	1		ENSP00000482568.2
ORAI1	ENST00000611718.1	n.708A>G		non_coding_transcript_exon_variant	2/2	5
ORAI1	ENST00000646827.1	n.850A>G		non_coding_transcript_exon_variant	2/2
ORAI1	ENST00000698901.1	n.774A>G		non_coding_transcript_exon_variant	2/2

Frequencies

GnomAD3 genomes AF: 0.0296 AC: 4502 AN: 152194 Hom.: 180 Cov.: 33

Gnomad AFR AF: 0.0764

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0122

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.112

Gnomad SAS AF: 0.0108

Gnomad FIN AF: 0.00489

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00593

Gnomad OTH AF: 0.0234

GnomAD3 exomes AF: 0.0166 AC: 4108 AN: 248022 Hom.: 151 AF XY: 0.0148 AC XY: 1992 AN XY: 134700

Gnomad AFR exome AF: 0.0771

Gnomad AMR exome AF: 0.00652

Gnomad ASJ exome AF: 0.00279

Gnomad EAS exome AF: 0.0909

Gnomad SAS exome AF: 0.00625

Gnomad FIN exome AF: 0.00608

Gnomad NFE exome AF: 0.00566

Gnomad OTH exome AF: 0.0124

GnomAD4 exome AF: 0.0123 AC: 17954 AN: 1461524 Hom.: 694 Cov.: 34 AF XY: 0.0119 AC XY: 8667 AN XY: 727106

Gnomad4 AFR exome AF: 0.0802

Gnomad4 AMR exome AF: 0.00664

Gnomad4 ASJ exome AF: 0.00214

Gnomad4 EAS exome AF: 0.149

Gnomad4 SAS exome AF: 0.00695

Gnomad4 FIN exome AF: 0.00566

Gnomad4 NFE exome AF: 0.00642

Gnomad4 OTH exome AF: 0.0153

GnomAD4 genome AF: 0.0296 AC: 4512 AN: 152310 Hom.: 181 Cov.: 33 AF XY: 0.0296 AC XY: 2208 AN XY: 74492

Gnomad4 AFR AF: 0.0764

Gnomad4 AMR AF: 0.0122

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.112

Gnomad4 SAS AF: 0.0112

Gnomad4 FIN AF: 0.00489

Gnomad4 NFE AF: 0.00593

Gnomad4 OTH AF: 0.0232

Alfa AF: 0.0130 Hom.: 32

Bravo AF: 0.0317

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.0686 AC: 301

ESP6500EA AF: 0.00595 AC: 51

ExAC AF: 0.0178 AC: 2164

Asia WGS AF: 0.0580 AC: 202 AN: 3478

EpiCase AF: 0.00556

EpiControl AF: 0.00551

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 13, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Combined immunodeficiency due to ORAI1 deficiency;C4014557:Myopathy, tubular aggregate, 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	0.090
DANN	Benign	0.42
DEOGEN2	Benign	0.18	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0035	N
LIST_S2	Benign	0.12	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PrimateAI	Benign	0.31	T
Polyphen		0.0	B
ClinPred		0.0059	T
GERP RS		-0.99
Varity_R		0.031
gMVP		0.47

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

Publications

LitVar

Other links and lift over

dbSNP: rs3741596; hg19: chr12-122079295;