7-102446841-C-A

Position:

• chr7-102446841-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001126340.3(ORAI2):​c.554C>A​(p.Pro185Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ORAI2 NM_001126340.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.116

Genes affected

ORAI2 (HGNC:21667): (ORAI calcium release-activated calcium modulator 2) Predicted to enable store-operated calcium channel activity. Predicted to be involved in store-operated calcium entry. Predicted to be located in growth cone. Predicted to be integral component of membrane. Predicted to be active in membrane. [provided by Alliance of Genome Resources, Apr 2022]

ORAI2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1213384).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ORAI2	NM_001126340.3	c.554C>A	p.Pro185Gln	missense_variant	4/4	ENST00000495936.7	NP_001119812.1
ORAI2	NM_001271818.2	c.554C>A	p.Pro185Gln	missense_variant	4/4		NP_001258747.1
ORAI2	NM_032831.4	c.554C>A	p.Pro185Gln	missense_variant	3/3		NP_116220.1
ORAI2	NM_001271819.2	c.323C>A	p.Pro108Gln	missense_variant	3/3		NP_001258748.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ORAI2	ENST00000495936.7	c.554C>A	p.Pro185Gln	missense_variant	4/4	2	NM_001126340.3	ENSP00000420178.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461478 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727066

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 27, 2023

The c.554C>A (p.P185Q) alteration is located in exon 4 (coding exon 2) of the ORAI2 gene. This alteration results from a C to A substitution at nucleotide position 554, causing the proline (P) at amino acid position 185 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.28
DANN	Benign	0.90
DEOGEN2	Benign	0.20	T;T;T;T;T;T;T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.63	.;T;T;.;T;.;.
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.12	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L;.;L;.;L;L
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.2	.;N;N;N;N;N;N
REVEL	Benign	0.025
Sift	Uncertain	0.022	.;D;D;D;D;D;D
Sift4G	Benign	0.081	T;T;T;T;T;T;T
Polyphen		0.011	B;B;.;B;.;B;B
Vest4		0.15
MutPred		0.32		Loss of glycosylation at P185 (P = 0.0021);Loss of glycosylation at P185 (P = 0.0021);Loss of glycosylation at P185 (P = 0.0021);Loss of glycosylation at P185 (P = 0.0021);Loss of glycosylation at P185 (P = 0.0021);Loss of glycosylation at P185 (P = 0.0021);Loss of glycosylation at P185 (P = 0.0021);
MVP		0.27
MPC		0.70
ClinPred		0.029	T
GERP RS		0.65
Varity_R		0.029
gMVP		0.49

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: rs766937231; hg19: chr7-102087288;