rs376614345
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_005027.4(PIK3R2):c.1290+4C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000117 in 1,613,724 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000085 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00012 ( 0 hom. )
Consequence
PIK3R2
NM_005027.4 splice_donor_region, intron
NM_005027.4 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.0002509
2
Clinical Significance
Conservation
PhyloP100: -2.18
Genes affected
PIK3R2 (HGNC:8980): (phosphoinositide-3-kinase regulatory subunit 2) Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase that phosphorylates phosphatidylinositol and similar compounds, creating second messengers important in growth signaling pathways. PI3K functions as a heterodimer of a regulatory and a catalytic subunit. The protein encoded by this gene is a regulatory component of PI3K. Three transcript variants, one protein coding and the other two non-protein coding, have been found for this gene. [provided by RefSeq, Apr 2019]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -13 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.83).
BP6
?
Variant 19-18163151-C-T is Benign according to our data. Variant chr19-18163151-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235355.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
BS1
?
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000855 (13/152118) while in subpopulation SAS AF= 0.000207 (1/4824). AF 95% confidence interval is 0.0000584. There are 0 homozygotes in gnomad4. There are 4 alleles in male gnomad4 subpopulation. This position pass quality control queck.
BS2
?
High AC in GnomAd at 13 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PIK3R2 | NM_005027.4 | c.1290+4C>T | splice_donor_region_variant, intron_variant | ENST00000222254.13 | |||
PIK3R2 | NR_073517.2 | n.1845+4C>T | splice_donor_region_variant, intron_variant, non_coding_transcript_variant | ||||
PIK3R2 | NR_162071.1 | n.1628+4C>T | splice_donor_region_variant, intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PIK3R2 | ENST00000222254.13 | c.1290+4C>T | splice_donor_region_variant, intron_variant | 1 | NM_005027.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000855 AC: 13AN: 152118Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000838 AC: 21AN: 250696Hom.: 0 AF XY: 0.0000738 AC XY: 10AN XY: 135536
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GnomAD4 exome AF: 0.000120 AC: 175AN: 1461606Hom.: 0 Cov.: 33 AF XY: 0.000120 AC XY: 87AN XY: 727072
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 02, 2024 | This sequence change falls in intron 10 of the PIK3R2 gene. It does not directly change the encoded amino acid sequence of the PIK3R2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs376614345, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with PIK3R2-related conditions. ClinVar contains an entry for this variant (Variation ID: 235355). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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 provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | May 06, 2016 | - - |
PIK3R2-related condition Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 08, 2020 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
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Prediction
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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Calibrated prediction
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at