rs75603737

chr12-121641405-A-Cchr12-121641405-A-Gchr12-121641405-A-T

Variant summary

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

The NM_032790.3(ORAI1):c.671A>C(p.Asn224Thr) 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 1,461,536 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict 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: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ORAI1 NM_032790.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.536

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]

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=0.086754054).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ORAI1	NM_032790.3	c.671A>C	p.Asn224Thr	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ORAI1	ENST00000617316.2	c.668A>C	p.Asn223Thr	missense_variant	3/3	1		P1
ORAI1	ENST00000611718.1	n.724A>C		non_coding_transcript_exon_variant	2/2	5
ORAI1	ENST00000646827.1	n.866A>C		non_coding_transcript_exon_variant	2/2
ORAI1	ENST00000698901.1	n.790A>C		non_coding_transcript_exon_variant	2/2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248572 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134946

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: 0.00

Gnomad NFE exome AF: 0.00000889

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461536 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727110

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	5.7
Dann	Benign	0.25
DEOGEN2	Benign	0.25	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.0014	T
MetaRNN	Benign	0.087	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.44	T
Polyphen		0.0	B
MutPred		0.47		Gain of catalytic residue at S227 (P = 2e-04);
MVP		0.20
ClinPred		0.034	T
GERP RS		0.59
Varity_R		0.067
gMVP		0.58

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: rs75603737; hg19: chr12-122079311;