3-179199700-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_006218.4(PIK3CA):c.363C>T(p.Ile121=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00879 in 1,605,692 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0075 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0089 ( 71 hom. )

Consequence

PIK3CA
NM_006218.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -1.73

Variant links:

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]

PIK3CA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BP6

Variant 3-179199700-C-T is Benign according to our data. Variant chr3-179199700-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 220946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-179199700-C-T is described in Lovd as [Benign]. Variant chr3-179199700-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-1.73 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00747 (1136/152100) while in subpopulation AMR AF= 0.0133 (204/15284). AF 95% confidence interval is 0.0118. There are 7 homozygotes in gnomad4. There are 525 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 7 SM gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3CA	NM_006218.4 linkuse as main transcript	c.363C>T	p.Ile121=	synonymous_variant	3/21	ENST00000263967.4
PIK3CA	XM_006713658.5 linkuse as main transcript	c.363C>T	p.Ile121=	synonymous_variant	3/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
PIK3CA	ENST00000263967.4 linkuse as main transcript	c.363C>T	p.Ile121=	synonymous_variant	3/21	2	NM_006218.4	P1
PIK3CA	ENST00000643187.1 linkuse as main transcript	c.363C>T	p.Ile121=	synonymous_variant	3/22
PIK3CA	ENST00000675467.1 linkuse as main transcript	n.3170C>T		non_coding_transcript_exon_variant	2/20
PIK3CA	ENST00000675786.1 linkuse as main transcript	c.363C>T	p.Ile121=	synonymous_variant, NMD_transcript_variant	3/21

Frequencies

GnomAD3 genomes

AF:

0.00747

AC:

1136

AN:

151984

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00196

Gnomad AMI

AF:

0.0417

Gnomad AMR

AF:

0.0134

Gnomad ASJ

AF:

0.0176

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00133

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0103

Gnomad OTH

AF:

0.0177

GnomAD3 exomes

AF:

0.00737

AC:

1836

AN:

249246

Hom.:

AF XY:

0.00723

AC XY:

978

AN XY:

135242

show subpopulations

Gnomad AFR exome

AF:

0.00181

Gnomad AMR exome

AF:

0.00910

Gnomad ASJ exome

AF:

0.0214

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000785

Gnomad FIN exome

AF:

0.00204

Gnomad NFE exome

AF:

0.0101

Gnomad OTH exome

AF:

0.0104

GnomAD4 exome

AF:

0.00892

AC:

12972

AN:

1453592

Hom.:

Cov.:

AF XY:

0.00871

AC XY:

6299

AN XY:

723544

show subpopulations

Gnomad4 AFR exome

AF:

0.00168

Gnomad4 AMR exome

AF:

0.00917

Gnomad4 ASJ exome

AF:

0.0214

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000674

Gnomad4 FIN exome

AF:

0.00184

Gnomad4 NFE exome

AF:

0.0101

Gnomad4 OTH exome

AF:

0.00962

GnomAD4 genome

AF:

0.00747

AC:

1136

AN:

152100

Hom.:

Cov.:

AF XY:

0.00706

AC XY:

525

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.00195

Gnomad4 AMR

AF:

0.0133

Gnomad4 ASJ

AF:

0.0176

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00133

Gnomad4 NFE

AF:

0.0103

Gnomad4 OTH

AF:

0.0175

Alfa

AF:

0.0110

Hom.:

Bravo

AF:

0.00829

Asia WGS

AF:

0.000289

AC:

AN:

3476

EpiCase

AF:

0.0106

EpiControl

AF:

0.0109

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 24, 2018	- -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	PIK3CA: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 05, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 04, 2019	- -

PIK3CA-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 10, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 12, 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 5

Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Cowden syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

Cadd

Benign

5.1

Dann

Benign

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over