rs200768351

Positions:

• chr3-179220061-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4 BP7 BS1

This summary comes from the ClinGen Evidence Repository: The c.2015+9A>G (NM_006218.4) variant in PIK3CA is an intronic variant. The highest population minor allele frequency in gnomAD v2.1.1 is 0.0008591 in the African/African American population, which is higher than the ClinGen BMEP threshold ([>0.00037]) for BS1, and therefore meets this criterion (BS1). The results from in silico splicing predictors MaxEntScan, spliceAI and varSEAK support that this variant does not affect splicing (BP4). This variant is a synonymous (silent) variant that occurs at a nucleotide that is not conserved according to a PhyloP <0.1 (BP7). 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: BS1, BP4, BP7; -6 points (VCEP specifications version 1; Approved: 1/31/2021) LINK:https://erepo.genome.network/evrepo/ui/classification/CA2710843/MONDO:0016054/018

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: PIK3CA NM_006218.4 intron
• Clinical Significance: Likely benign reviewed by expert panel B:3
• Conservation: PhyloP100: -0.210

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIK3CA	NM_006218.4	c.2015+9A>G		intron_variant		ENST00000263967.4	NP_006209.2
PIK3CA	XM_006713658.5	c.2015+9A>G		intron_variant			XP_006713721.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIK3CA	ENST00000263967.4	c.2015+9A>G		intron_variant		2	NM_006218.4	ENSP00000263967.3

Frequencies

GnomAD3 genomes AF: 0.000316 AC: 48 AN: 151978 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000110 AC: 24 AN: 218450 Hom.: 0 AF XY: 0.0000586 AC XY: 7 AN XY: 119426

Gnomad AFR exome AF: 0.000892

Gnomad AMR exome AF: 0.000357

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000962

Gnomad OTH exome AF: 0.000196

GnomAD4 exome AF: 0.0000301 AC: 42 AN: 1397242 Hom.: 0 Cov.: 26 AF XY: 0.0000144 AC XY: 10 AN XY: 694706

Gnomad4 AFR exome AF: 0.000745

Gnomad4 AMR exome AF: 0.000227

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000129

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000558

Gnomad4 OTH exome AF: 0.0000692

GnomAD4 genome AF: 0.000316 AC: 48 AN: 152096 Hom.: 0 Cov.: 32 AF XY: 0.000323 AC XY: 24 AN XY: 74364

Gnomad4 AFR AF: 0.00108

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000287

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: reviewed by expert panel

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 12, 2022

The c.2015+9A>G (NM_006218.4) variant in PIK3CA is an intronic variant. The highest population minor allele frequency in gnomAD v2.1.1 is 0.0008591 in the African/African American population, which is higher than the ClinGen BMEP threshold ([>0.00037]) for BS1, and therefore meets this criterion (BS1). The results from in silico splicing predictors MaxEntScan, spliceAI and varSEAK support that this variant does not affect splicing (BP4). This variant is a synonymous (silent) variant that occurs at a nucleotide that is not conserved according to a PhyloP <0.1 (BP7). 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: BS1, BP4, BP7; -6 points (VCEP specifications version 1; Approved: 1/31/2021) -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 08, 2020

- -

Cowden syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.4
DANN	Benign	0.72

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

Publications

LitVar

Other links and lift over

dbSNP: rs200768351; hg19: chr3-178937849;