3-179221010-T-C
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM2BP4_StrongBP6_Very_StrongBP7
The NM_006218.4(PIK3CA):c.2040T>C(p.Val680=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,612,688 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 Likely benign (★★★).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000024 ( 0 hom. )
Consequence
PIK3CA
NM_006218.4 synonymous
NM_006218.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.532
Genes affected
PIK3CA (HGNC:8975): (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) Phosphatidylinositol 3-kinase is composed of an 85 kDa regulatory subunit and a 110 kDa catalytic subunit. The protein encoded by this gene represents the catalytic subunit, which uses ATP to phosphorylate PtdIns, PtdIns4P and PtdIns(4,5)P2. This gene has been found to be oncogenic and has been implicated in cervical cancers. A pseudogene of this gene has been defined on chromosome 22. [provided by RefSeq, Apr 2016]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -11 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.75).
BP6
?
Variant 3-179221010-T-C is Benign according to our data. Variant chr3-179221010-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 456534.Status of the report is reviewed_by_expert_panel, 3 stars.
BP7
?
Synonymous conserved (PhyloP=-0.532 with no splicing effect.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PIK3CA | NM_006218.4 | c.2040T>C | p.Val680= | synonymous_variant | 14/21 | ENST00000263967.4 | |
PIK3CA | XM_006713658.5 | c.2040T>C | p.Val680= | synonymous_variant | 14/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PIK3CA | ENST00000263967.4 | c.2040T>C | p.Val680= | synonymous_variant | 14/21 | 2 | NM_006218.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152180Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000804 AC: 2AN: 248908Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135044
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GnomAD4 exome AF: 0.0000240 AC: 35AN: 1460508Hom.: 0 Cov.: 30 AF XY: 0.0000206 AC XY: 15AN XY: 726558
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GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152180Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74338
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ClinVar
Significance: Likely benign
Submissions summary: Benign:3
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes Benign:1
Likely benign, reviewed by expert panel | curation | ClinGen Brain Malformations Variant Curation Expert Panel | Feb 11, 2022 | The NM_006218.4(PIK3CA): c.2040T>C (p.Val680=) variant is a synonymous (silent) variant that occurs at a nucleotide that is not conserved according to a PhyloP <0.1 (BP7). The results from in silico splicing predictors MaxEntScan, spliceAI and varSEAK support that this variant does not affect splicing (BP4). In summary, this variant meets the criteria to be classified as Likely benign for mosaic autosomal dominant overgrowth with or without cerebral malformations due to abnormalities in MTOR-pathway genes based on the ACMG/AMP criteria applied, as specified by the ClinGen Brain Malformations Expert Panel: BP4, BP7; -2 points (VCEP specifications version 1; Approved: 1/31/2021) - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 16, 2022 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Cowden syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Nov 05, 2023 | - - |
Computational scores
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BayesDel_noAF
Benign
Cadd
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Dann
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at