Genetic Variant NM_001126340.3:c.28G>C (chr7-102438984-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001126340.3(ORAI2):c.28G>C(p.Asp10His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ORAI2
NM_001126340.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.70

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.34111542).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ORAI2	NM_001126340.3 link	c.28G>C	p.Asp10His	missense_variant	Exon 3 of 4	ENST00000495936.7	NP_001119812.1	Q96SN7
ORAI2	NM_001271818.2 link	c.28G>C	p.Asp10His	missense_variant	Exon 3 of 4		NP_001258747.1	Q96SN7
ORAI2	NM_032831.4 link	c.28G>C	p.Asp10His	missense_variant	Exon 2 of 3		NP_116220.1	Q96SN7
ORAI2	NM_001271819.2 link	c.-7+2651G>C		intron_variant	Intron 2 of 2		NP_001258748.1	B4DUB4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ORAI2	ENST00000495936.7 link	c.28G>C	p.Asp10His	missense_variant	Exon 3 of 4	2	NM_001126340.3	ENSP00000420178.2		Q96SN7C9JQR7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251072

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135846

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461742

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727174

show subpopulations

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:

0.0000375

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.081

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.15

T;T;T;T;T;T;T;.;T

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.92

D;.;D;D;.;D;.;D;.

M_CAP

Benign

0.034

MetaRNN

Benign

0.34

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

1.1

.;L;L;.;L;.;L;.;L

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-6.7

D;.;N;N;N;N;N;N;N

REVEL

Benign

0.13

Sift

Uncertain

0.0040

D;.;T;T;T;D;T;T;T

Sift4G

Pathogenic

0.0

D;T;T;T;T;T;T;T;T

Polyphen

0.80

.;P;P;.;P;.;P;.;P

Vest4

0.28, 0.28

MutPred

0.13

Loss of disorder (P = 0.1059);Loss of disorder (P = 0.1059);Loss of disorder (P = 0.1059);Loss of disorder (P = 0.1059);Loss of disorder (P = 0.1059);Loss of disorder (P = 0.1059);Loss of disorder (P = 0.1059);Loss of disorder (P = 0.1059);Loss of disorder (P = 0.1059);

MVP

0.80

MPC

1.3

ClinPred

0.79

GERP RS

5.4

Varity_R

0.057

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over