Genetic Variant ORAI1:p.Ser34Gly (chr12-121626842-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000617316.2(ORAI1):c.100A>G(p.Ser34Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000739 in 1,354,048 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S34R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Consequence

ORAI1
ENST00000617316.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.29

Publications

0 publications found

Variant links:

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: Orphanet, Labcorp Genetics (formerly Invitae)
Stormorken syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ORAI1 links:

ENSG00000302371 (HGNC:):

ENSG00000302371 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19448572).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ORAI1	NR_186857.1 link	n.313A>G		non_coding_transcript_exon_variant	Exon 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ORAI1	ENST00000617316.2 link	c.100A>G	p.Ser34Gly	missense_variant	Exon 1 of 3	1		ENSP00000482568.2		Q96D31-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.39e-7

AC:

AN:

1354048

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

670510

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27486

American (AMR)

AF:

0.00

AC:

AN:

28950

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23266

East Asian (EAS)

AF:

0.00

AC:

AN:

30830

South Asian (SAS)

AF:

0.00

AC:

AN:

75060

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47828

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4914

European-Non Finnish (NFE)

AF:

9.43e-7

AC:

AN:

1060386

Other (OTH)

AF:

0.00

AC:

AN:

55328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.069

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.095

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.39

M_CAP

Pathogenic

0.47

MetaRNN

Benign

0.19

MetaSVM

Benign

-1.1

PhyloP100

2.3

PrimateAI

Pathogenic

0.92

Polyphen

0.23

MutPred

0.17

Loss of phosphorylation at S34 (P = 1e-04);

ClinPred

0.85

GERP RS

3.8

PromoterAI

0.052

Neutral

(source)

Varity_R

0.24

gMVP

0.56

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over