chr12-121627039-G-A

Position:

• chr12-121627039-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_032790.3(ORAI1):​c.295G>A​(p.Gly99Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ORAI1 NM_032790.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.67

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956
• PP5: Variant 12-121627039-G-A is Pathogenic according to our data. Variant chr12-121627039-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 189256.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ORAI1	NM_032790.3	c.295G>A	p.Gly99Ser	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ORAI1	ENST00000617316.2	c.292G>A	p.Gly98Ser	missense_variant	2/3	1		P1
ORAI1	ENST00000611718.1	n.224G>A		non_coding_transcript_exon_variant	1/2	5
ORAI1	ENST00000646827.1	n.490G>A		non_coding_transcript_exon_variant	1/2
ORAI1	ENST00000698901.1	n.425+106G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Myopathy, tubular aggregate, 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2015

- -

Myopathy with tubular aggregates Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire

Mar 01, 2024

PS3+PM2+PM6+PP3+PP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.88	D
Polyphen		1.0	D
MutPred		0.79		Gain of catalytic residue at A100 (P = 0.0125);
MVP		0.46
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.69
gMVP		0.86

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: rs786204796; hg19: chr12-122064945;