chr3-179226113-C-G

Variant names:

• chr3-179226113-C-G
• rs1356413
• NM_006218.4:c.2495+73C>G

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.2495+73C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0504 in 760,876 control chromosomes in the GnomAD database, including 1,128 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (252 hom., cov: 32)
  • Exomes 𝑓: 0.050 (876 hom.)
• Consequence: PIK3CA NM_006218.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.260
• Publications: 3 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=-0.84).
• BP6: Variant 3-179226113-C-G is Benign according to our data. Variant chr3-179226113-C-G is described in ClinVar as Benign. ClinVar VariationId is 1269218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0642 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3CA	NM_006218.4	MANE Select	c.2495+73C>G		intron	N/A	NP_006209.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3CA	ENST00000263967.4	TSL:2 MANE Select	c.2495+73C>G		intron	N/A	ENSP00000263967.3
	PIK3CA	ENST00000643187.1		c.2495+73C>G		intron	N/A	ENSP00000493507.1
	PIK3CA	ENST00000462255.2	TSL:3	n.957+73C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0503 AC: 7649 AN: 151926 Hom.: 251 Cov.: 32

Gnomad AFR AF: 0.0545

Gnomad AMI AF: 0.0549

Gnomad AMR AF: 0.0678

Gnomad ASJ AF: 0.0742

Gnomad EAS AF: 0.0521

Gnomad SAS AF: 0.0475

Gnomad FIN AF: 0.0318

Gnomad MID AF: 0.186

Gnomad NFE AF: 0.0442

Gnomad OTH AF: 0.0757

GnomAD4 exome AF: 0.0504 AC: 30705 AN: 608832 Hom.: 876 AF XY: 0.0501 AC XY: 16299 AN XY: 325054

African (AFR) AF: 0.0600 AC: 960 AN: 16006

American (AMR) AF: 0.0776 AC: 2799 AN: 36080

Ashkenazi Jewish (ASJ) AF: 0.0773 AC: 1430 AN: 18492

East Asian (EAS) AF: 0.0545 AC: 1831 AN: 33586

South Asian (SAS) AF: 0.0491 AC: 2938 AN: 59878

European-Finnish (FIN) AF: 0.0350 AC: 1665 AN: 47590

Middle Eastern (MID) AF: 0.152 AC: 602 AN: 3954

European-Non Finnish (NFE) AF: 0.0464 AC: 16814 AN: 361994

Other (OTH) AF: 0.0533 AC: 1666 AN: 31252

GnomAD4 genome AF: 0.0504 AC: 7658 AN: 152044 Hom.: 252 Cov.: 32 AF XY: 0.0502 AC XY: 3728 AN XY: 74318

African (AFR) AF: 0.0546 AC: 2265 AN: 41480

American (AMR) AF: 0.0677 AC: 1031 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.0742 AC: 257 AN: 3464

East Asian (EAS) AF: 0.0521 AC: 269 AN: 5166

South Asian (SAS) AF: 0.0479 AC: 231 AN: 4820

European-Finnish (FIN) AF: 0.0318 AC: 337 AN: 10584

Middle Eastern (MID) AF: 0.190 AC: 55 AN: 290

European-Non Finnish (NFE) AF: 0.0442 AC: 3004 AN: 67984

Other (OTH) AF: 0.0754 AC: 159 AN: 2108

Alfa AF: 0.0439 Hom.: 22

Bravo AF: 0.0542

Asia WGS AF: 0.0540 AC: 186 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 13, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	9.9
DANN	Benign	0.34
PhyloP100		0.26
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: rs1356413; hg19: chr3-178943901; COSMIC: COSV104381260;