rs3729692

Variant names:

• chr3-179229537-A-C
• rs3729692
• NM_006218.4:c.2666+95A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006218.4(PIK3CA):​c.2666+95A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0495 in 834,288 control chromosomes in the GnomAD database, including 1,210 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (215 hom., cov: 32)
  • Exomes 𝑓: 0.049 (995 hom.)
• Consequence: PIK3CA NM_006218.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.697
• Publications: 12 publications found

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 Gene-Disease associations (from GenCC):

• overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• megalencephaly-capillary malformation-polymicrogyria syndrome

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• vascular malformation

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• Cowden disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cowden syndrome 5

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 3-179229537-A-C is Benign according to our data. Variant chr3-179229537-A-C is described in ClinVar as Benign. ClinVar VariationId is 1183698.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0558 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3CA	NM_006218.4	c.2666+95A>C		intron_variant	Intron 18 of 20	ENST00000263967.4	NP_006209.2
PIK3CA	XM_006713658.5	c.2666+95A>C		intron_variant	Intron 18 of 20		XP_006713721.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3CA	ENST00000263967.4	c.2666+95A>C		intron_variant	Intron 18 of 20	2	NM_006218.4	ENSP00000263967.3

Frequencies

GnomAD3 genomes AF: 0.0511 AC: 7780 AN: 152136 Hom.: 216 Cov.: 32

Gnomad AFR AF: 0.0420

Gnomad AMI AF: 0.0549

Gnomad AMR AF: 0.0514

Gnomad ASJ AF: 0.0867

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0118

Gnomad FIN AF: 0.0743

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0573

Gnomad OTH AF: 0.0694

GnomAD4 exome AF: 0.0492 AC: 33529 AN: 682034 Hom.: 995 AF XY: 0.0483 AC XY: 16611 AN XY: 343978

African (AFR) AF: 0.0429 AC: 693 AN: 16152

American (AMR) AF: 0.0472 AC: 645 AN: 13670

Ashkenazi Jewish (ASJ) AF: 0.0866 AC: 1239 AN: 14310

East Asian (EAS) AF: 0.0000666 AC: 2 AN: 30052

South Asian (SAS) AF: 0.0114 AC: 422 AN: 36992

European-Finnish (FIN) AF: 0.0596 AC: 2406 AN: 40398

Middle Eastern (MID) AF: 0.0497 AC: 169 AN: 3398

European-Non Finnish (NFE) AF: 0.0530 AC: 26233 AN: 494598

Other (OTH) AF: 0.0530 AC: 1720 AN: 32464

GnomAD4 genome AF: 0.0511 AC: 7781 AN: 152254 Hom.: 215 Cov.: 32 AF XY: 0.0509 AC XY: 3791 AN XY: 74418

African (AFR) AF: 0.0419 AC: 1742 AN: 41572

American (AMR) AF: 0.0514 AC: 785 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0867 AC: 301 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.0118 AC: 57 AN: 4826

European-Finnish (FIN) AF: 0.0743 AC: 787 AN: 10588

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0573 AC: 3899 AN: 68010

Other (OTH) AF: 0.0682 AC: 144 AN: 2112

Alfa AF: 0.0599 Hom.: 436

Bravo AF: 0.0506

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.0
DANN	Benign	0.70
PhyloP100		0.70
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3729692; hg19: chr3-178947325; COSMIC: COSV104381071;