chr12-121626756-C-T
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1
The NM_032790.3(ORAI1):c.14C>T(p.Pro5Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000142 in 1,229,770 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00015 ( 0 hom., cov: 30)
Exomes 𝑓: 0.00014 ( 1 hom. )
Consequence
ORAI1
NM_032790.3 missense
NM_032790.3 missense
Scores
2
1
11
Clinical Significance
Conservation
PhyloP100: 0.463
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -7 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.049255908).
BP6
?
Variant 12-121626756-C-T is Benign according to our data. Variant chr12-121626756-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 854069.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000146 (22/150260) while in subpopulation NFE AF= 0.000223 (15/67210). AF 95% confidence interval is 0.000138. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ORAI1 | NM_032790.3 | c.14C>T | p.Pro5Leu | missense_variant | 1/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ORAI1 | ENST00000617316.2 | c.14C>T | p.Pro5Leu | missense_variant | 1/3 | 1 | P1 | ||
ORAI1 | ENST00000646827.1 | n.207C>T | non_coding_transcript_exon_variant | 1/2 | |||||
ORAI1 | ENST00000698901.1 | n.248C>T | non_coding_transcript_exon_variant | 1/2 |
Frequencies
GnomAD3 genomes ? AF: 0.000147 AC: 22AN: 150150Hom.: 0 Cov.: 30
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GnomAD3 exomes AF: 0.000124 AC: 1AN: 8060Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 3972
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GnomAD4 exome AF: 0.000142 AC: 153AN: 1079510Hom.: 1 Cov.: 29 AF XY: 0.000169 AC XY: 87AN XY: 515362
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Combined immunodeficiency due to ORAI1 deficiency;C4014557:Myopathy, tubular aggregate, 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 5 of the ORAI1 protein (p.Pro5Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with ORAI1-related conditions. ClinVar contains an entry for this variant (Variation ID: 854069). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 16, 2024 | Variant summary: ORAI1 c.14C>T (p.Pro5Leu) results in a non-conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 1,225,808 control chromosomes in the gnomAD database (v4.0 dataset), including 1 homozygote. The occurrence in several carriers suggests that this variant is likely not associated with a high penetrance, severe, early onset disease phenotype in heterozygous state. c.14C>T has been reported in the literature in an individual affected with multiple sclerosis, however this patient also carried several other variants (Jafarpour_2022). This report does not provide unequivocal conclusions about association of the variant with Myopathy, Tubular Aggregate, 2. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 35960392). ClinVar contains an entry for this variant (Variation ID: 854069). Based on the evidence outlined above, the variant was classified as likely benign. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 07, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T
M_CAP
Pathogenic
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
Polyphen
B
MutPred
Gain of catalytic residue at E4 (P = 0.0149);
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at