chr7-102446912-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001126340.3(ORAI2):​c.625C>T​(p.Leu209Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 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. L209V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ORAI2 NM_001126340.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.28
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3630867).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001126340.3. 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
	ORAI2	NM_001126340.3	MANE Select	c.625C>T	p.Leu209Phe	missense	Exon 4 of 4	NP_001119812.1	Q96SN7
	ORAI2	NM_001271818.2		c.625C>T	p.Leu209Phe	missense	Exon 4 of 4	NP_001258747.1	Q96SN7
	ORAI2	NM_032831.4		c.625C>T	p.Leu209Phe	missense	Exon 3 of 3	NP_116220.1	Q96SN7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORAI2	ENST00000495936.7	TSL:2 MANE Select	c.625C>T	p.Leu209Phe	missense	Exon 4 of 4	ENSP00000420178.2	Q96SN7
	ORAI2	ENST00000473939.2	TSL:1	c.625C>T	p.Leu209Phe	missense	Exon 3 of 3	ENSP00000417928.1	Q96SN7
	ORAI2	ENST00000498661.6	TSL:1	c.625C>T	p.Leu209Phe	missense	Exon 3 of 3	ENSP00000418464.2	Q96SN7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460862 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726762

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52502

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111944

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.17
FATHMM_MKL	Benign	0.50	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.66	N
PhyloP100		1.3
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.13
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.033	D
Polyphen		0.75	P
Vest4		0.17
MutPred		0.68		Loss of MoRF binding (P = 0.2459)
MVP		0.59
MPC		1.3
ClinPred		0.48	T
GERP RS		4.7
Varity_R		0.14
gMVP		0.88
Mutation Taster		=73/27	polymorphism

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

Other links and lift over

dbSNP: rs1797385372; hg19: chr7-102087359;