rs1372064351

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The ENST00000617316.2(ORAI1):c.85_99dupCGGAGCCGCCGCCGC(p.Arg29_Arg33dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00011 in 1,396,024 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S34S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000097 ( 0 hom. )

Consequence

ORAI1
ENST00000617316.2 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 3.21

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 2 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in ENST00000617316.2.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ORAI1	NR_186857.1 link	n.298_312dupCGGAGCCGCCGCCGC		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.85_99dupCGGAGCCGCCGCCGC	p.Arg29_Arg33dup	conservative_inframe_insertion	Exon 1 of 3	1		ENSP00000482568.2

Frequencies

GnomAD3 genomes

AF:

0.000215

AC:

AN:

148632

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000667

Gnomad ASJ

AF:

0.00783

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000300

Gnomad OTH

AF:

0.000981

GnomAD2 exomes

AF:

0.00

AC:

AN:

41686

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000970

AC:

121

AN:

1247392

Hom.:

Cov.:

AF XY:

0.0000963

AC XY:

AN XY:

612578

show subpopulations

African (AFR)

AF:

0.0000420

AC:

AN:

23802

American (AMR)

AF:

0.0000788

AC:

AN:

12686

Ashkenazi Jewish (ASJ)

AF:

0.00375

AC:

AN:

17890

East Asian (EAS)

AF:

0.00

AC:

AN:

27530

South Asian (SAS)

AF:

0.00

AC:

AN:

57682

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4236

European-Non Finnish (NFE)

AF:

0.0000367

AC:

AN:

1008600

Other (OTH)

AF:

0.000297

AC:

AN:

50584

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.413

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

AF:

0.000215

AC:

AN:

148632

Hom.:

Cov.:

AF XY:

0.000179

AC XY:

AN XY:

72532

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40640

American (AMR)

AF:

0.0000667

AC:

AN:

14986

Ashkenazi Jewish (ASJ)

AF:

0.00783

AC:

AN:

3448

East Asian (EAS)

AF:

0.00

AC:

AN:

4936

South Asian (SAS)

AF:

0.00

AC:

AN:

4782

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9828

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000300

AC:

AN:

66760

Other (OTH)

AF:

0.000981

AC:

AN:

2038

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000590

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Sep 27, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM4 -

May 18, 2023

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Uncertain:1

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.85_99dup, results in the insertion of 5 amino acid(s) of the ORAI1 protein (p.Arg29_Arg33dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (no rsID available, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with ORAI1-related conditions. ClinVar contains an entry for this variant (Variation ID: 541943). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.2

Mutation Taster

=89/11

polymorphism

(source)

Splicing

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over