7-102446912-C-G

Variant names:

• chr7-102446912-C-G
• rs1797385372
• NM_001126340.3:c.625C>G

Variant summary

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

The NM_001126340.3(ORAI2):​c.625C>G​(p.Leu209Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,460,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 0.000011 (0 hom.)
• Consequence: ORAI2 NM_001126340.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.28

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]

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=0.16267976).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ORAI2	NM_001126340.3	c.625C>G	p.Leu209Val	missense_variant	Exon 4 of 4	ENST00000495936.7	NP_001119812.1
ORAI2	NM_001271818.2	c.625C>G	p.Leu209Val	missense_variant	Exon 4 of 4		NP_001258747.1
ORAI2	NM_032831.4	c.625C>G	p.Leu209Val	missense_variant	Exon 3 of 3		NP_116220.1
ORAI2	NM_001271819.2	c.394C>G	p.Leu132Val	missense_variant	Exon 3 of 3		NP_001258748.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ORAI2	ENST00000495936.7	c.625C>G	p.Leu209Val	missense_variant	Exon 4 of 4	2	NM_001126340.3	ENSP00000420178.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1460862 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 726762

Gnomad4 AFR exome AF: 0.0000299

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: 0.0000135

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.625C>G (p.L209V) alteration is located in exon 4 (coding exon 2) of the ORAI2 gene. This alteration results from a C to G substitution at nucleotide position 625, causing the leucine (L) at amino acid position 209 to be replaced by a valine (V). 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	0.069
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.18	T;T;T;T;T;T;T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.94	.;D;D;.;D;.;.
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.16	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.28	N;N;.;N;.;N;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	0.45	.;N;N;N;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.39	.;T;T;T;T;T;T
Sift4G	Benign	0.83	T;T;T;T;T;T;T
Polyphen		0.0010	B;B;.;B;.;B;B
Vest4		0.18
MutPred		0.66		Gain of MoRF binding (P = 0.203);Gain of MoRF binding (P = 0.203);Gain of MoRF binding (P = 0.203);Gain of MoRF binding (P = 0.203);Gain of MoRF binding (P = 0.203);Gain of MoRF binding (P = 0.203);Gain of MoRF binding (P = 0.203);
MVP		0.45
MPC		0.77
ClinPred		0.12	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.060
gMVP		0.76

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: rs1797385372; hg19: chr7-102087359;