3-179206019-C-T

Variant names:

• chr3-179206019-C-T
• rs2677764
• NM_006218.4:c.1145+1431C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006218.4(PIK3CA):​c.1145+1431C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.069 in 151,626 control chromosomes in the GnomAD database, including 451 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. The gene PIK3CA is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: 𝑓 0.069 (451 hom., cov: 31)
• Consequence: PIK3CA NM_006218.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.43
• Publications: 14 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: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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)
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• familial ovarian cancer

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Specifications for PIK3CA are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0968 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006218.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3CA	NM_006218.4	MANE Select	c.1145+1431C>T		intron	N/A	NP_006209.2	P42336

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3CA	ENST00000263967.4	TSL:2 MANE Select	c.1145+1431C>T		intron	N/A	ENSP00000263967.3	P42336
	PIK3CA	ENST00000955190.1		c.1175+1431C>T		intron	N/A	ENSP00000625249.1
	PIK3CA	ENST00000876545.1		c.1145+1431C>T		intron	N/A	ENSP00000546604.1

Frequencies

GnomAD3 genomes AF: 0.0691 AC: 10466 AN: 151546 Hom.: 450 Cov.: 31

Gnomad AFR AF: 0.0173

Gnomad AMI AF: 0.0969

Gnomad AMR AF: 0.0736

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.0671

Gnomad SAS AF: 0.0528

Gnomad FIN AF: 0.0676

Gnomad MID AF: 0.0353

Gnomad NFE AF: 0.0988

Gnomad OTH AF: 0.0686

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0690 AC: 10463 AN: 151626 Hom.: 451 Cov.: 31 AF XY: 0.0675 AC XY: 4998 AN XY: 74048

African (AFR) AF: 0.0172 AC: 712 AN: 41300

American (AMR) AF: 0.0733 AC: 1116 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 371 AN: 3466

East Asian (EAS) AF: 0.0672 AC: 347 AN: 5160

South Asian (SAS) AF: 0.0529 AC: 253 AN: 4784

European-Finnish (FIN) AF: 0.0676 AC: 704 AN: 10416

Middle Eastern (MID) AF: 0.0313 AC: 9 AN: 288

European-Non Finnish (NFE) AF: 0.0988 AC: 6715 AN: 67974

Other (OTH) AF: 0.0703 AC: 148 AN: 2106

Alfa AF: 0.0838 Hom.: 730

Bravo AF: 0.0687

Asia WGS AF: 0.0620 AC: 216 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.61
DANN	Benign	0.48
PhyloP100		-1.4
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2677764;

hg19: chr3-178923807;