12-121627039-GGC-CGA

Variant names:

• chr12-121627039-GGC-CGA
• ENST00000617316.2:c.292_294delGGCinsCGA
• ORAI1 p.Gly98Arg

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM5 PP3

The ENST00000617316.2(ORAI1):​c.292_294delGGCinsCGA​(p.Gly98Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. 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. G98S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ORAI1 ENST00000617316.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.67
• Publications: 0 publications found

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: Labcorp Genetics (formerly Invitae), Orphanet
• Stormorken syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000302371 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in ENST00000617316.2
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-121627039-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 189256.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000617316.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORAI1	NR_186857.1		n.510_512delGGCinsCGA		non_coding_transcript_exon	Exon 1 of 2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORAI1	ENST00000617316.2	TSL:1	c.292_294delGGCinsCGA	p.Gly98Arg	missense	N/A	ENSP00000482568.2	Q96D31-1
	ORAI1	ENST00000611718.1	TSL:5	n.224_226delGGCinsCGA		non_coding_transcript_exon	Exon 1 of 2
	ORAI1	ENST00000646827.1		n.490_492delGGCinsCGA		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.7

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr12-122064945;