chr12-121626888-G-GCCGCCGCCGCAGCGGGGACGGGGAGCCCCCGGGGGCC

Position:

• chr12-121626888-G-GCCGCCGCCGCAGCGGGGACGGGGAGCCCCCGGGGGCC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The ENST00000617316.2(ORAI1):​c.141_142insCCGCCGCCGCAGCGGGGACGGGGAGCCCCCGGGGGCC​(p.Ser48fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ORAI1 ENST00000617316.2 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.140

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-121626888-G-GCCGCCGCCGCAGCGGGGACGGGGAGCCCCCGGGGGCC is Pathogenic according to our data. Variant chr12-121626888-G-GCCGCCGCCGCAGCGGGGACGGGGAGCCCCCGGGGGCC is described in ClinVar as [Pathogenic]. Clinvar id is 470188.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ORAI1	NR_186857.1	n.359_360insCCGCCGCCGCAGCGGGGACGGGGAGCCCCCGGGGGCC		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ORAI1	ENST00000617316.2	c.141_142insCCGCCGCCGCAGCGGGGACGGGGAGCCCCCGGGGGCC	p.Ser48fs	frameshift_variant	2/3	1		ENSP00000482568.2
ORAI1	ENST00000611718.1	n.73_74insCCGCCGCCGCAGCGGGGACGGGGAGCCCCCGGGGGCC		non_coding_transcript_exon_variant	1/2	5
ORAI1	ENST00000646827.1	n.339_340insCCGCCGCCGCAGCGGGGACGGGGAGCCCCCGGGGGCC		non_coding_transcript_exon_variant	1/2
ORAI1	ENST00000698901.1	n.380_381insCCGCCGCCGCAGCGGGGACGGGGAGCCCCCGGGGGCC		non_coding_transcript_exon_variant	1/2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Combined immunodeficiency due to ORAI1 deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 21, 2017

This sequence change results in a premature translational stop signal in the ORAI1 gene (p.Ser48Glnfs*52). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 254 amino acids (>80%) of the ORAI1 protein. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with an ORAI1-related disease. Loss-of function variants in ORAI1 are known to be causative of autosomal recessive ORAI1 deficiency. Truncating variants downstream of this variant (p.Ala88serfs*25, p.His165Profs*2, p.Arg268*) have been reported in homozygous and compound heterozygous individuals with ORAI1 deficiency and determined to be pathogenic (PMID: 26070885, 20004786, 27063589). This suggests that deletion of the C-terminal region of the ORAI1 protein is causative of disease. In summary, this is a novel insertion that leads to the disruption of most of the ORAI1 protein sequence, and truncating variants downstream from this variant have been shown to be deleterious. Therefore, it has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555322558; hg19: chr12-122064794;