chr12-121626791-C-T

Position:

chr12-121626791-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2BP4_StrongBP6_Very_StrongBS1

The ENST00000617316.2(ORAI1):c.49C>T(p.Pro17Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00032 in 1,360,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P17P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

ORAI1
ENST00000617316.2 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.510

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0074937046).

BP6

Variant 12-121626791-C-T is Benign according to our data. Variant chr12-121626791-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 541945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00136 (205/150772) while in subpopulation AFR AF= 0.00452 (187/41374). AF 95% confidence interval is 0.00399. There are 0 homozygotes in gnomad4. There are 93 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ORAI1	NM_032790.3 linkuse as main transcript	c.49C>T	p.Pro17Ser	missense_variant	1/3		NP_116179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	Protein	Appris	UniProt
ORAI1	ENST00000617316.2 linkuse as main transcript	c.49C>T	p.Pro17Ser	missense_variant	1/3	1	ENSP00000482568	P1	Q96D31-1
ORAI1	ENST00000646827.1 linkuse as main transcript	n.242C>T		non_coding_transcript_exon_variant	1/2
ORAI1	ENST00000698901.1 linkuse as main transcript	n.283C>T		non_coding_transcript_exon_variant	1/2
ORAI1	ENST00000611718.1 linkuse as main transcript			upstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00137

AC:

206

AN:

150664

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00456

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000989

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:

0.0000297

Gnomad OTH

AF:

0.000485

GnomAD3 exomes

AF:

0.0000857

AC:

AN:

23338

Hom.:

AF XY:

0.0000779

AC XY:

AN XY:

12832

show subpopulations

Gnomad AFR exome

AF:

0.00575

Gnomad AMR exome

AF:

0.000533

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.000190

AC:

230

AN:

1209820

Hom.:

Cov.:

AF XY:

0.000181

AC XY:

107

AN XY:

590592

show subpopulations

Gnomad4 AFR exome

AF:

0.00515

Gnomad4 AMR exome

AF:

0.000286

Gnomad4 ASJ exome

AF:

0.0000631

Gnomad4 EAS exome

AF:

0.0000387

Gnomad4 SAS exome

AF:

0.0000399

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000818

Gnomad4 OTH exome

AF:

0.000494

GnomAD4 genome

AF:

0.00136

AC:

205

AN:

150772

Hom.:

Cov.:

AF XY:

0.00126

AC XY:

AN XY:

73704

show subpopulations

Gnomad4 AFR

AF:

0.00452

Gnomad4 AMR

AF:

0.000988

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000297

Gnomad4 OTH

AF:

0.000480

Alfa

AF:

0.000143

Hom.:

Bravo

AF:

0.00141

ExAC

AF:

0.000227

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

ORAI1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 25, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.057

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.48

M_CAP

Pathogenic

0.76

MetaRNN

Benign

0.0075

MetaSVM

Benign

-1.0

MutationTaster

Benign

0.98

PrimateAI

Pathogenic

0.92

Polyphen

0.012

ClinPred

0.046

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.045

gMVP

0.69

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over