11-17091430-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002645.4(PIK3C2A):c.4782A>G(p.Pro1594=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00595 in 1,613,756 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0061 (48 hom.)
• Consequence: PIK3C2A NM_002645.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.242

Genes affected

PIK3C2A (HGNC:8971): (phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 alpha) The protein encoded by this gene belongs to the phosphoinositide 3-kinase (PI3K) family. PI3-kinases play roles in signaling pathways involved in cell proliferation, oncogenic transformation, cell survival, cell migration, and intracellular protein trafficking. This protein contains a lipid kinase catalytic domain as well as a C-terminal C2 domain, a characteristic of class II PI3-kinases. C2 domains act as calcium-dependent phospholipid binding motifs that mediate translocation of proteins to membranes, and may also mediate protein-protein interactions. The PI3-kinase activity of this protein is not sensitive to nanomolar levels of the inhibitor wortmanin. This protein was shown to be able to be activated by insulin and may be involved in integrin-dependent signaling. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 11-17091430-T-C is Benign according to our data. Variant chr11-17091430-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 1665149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.242 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00417 (635/152354) while in subpopulation NFE AF= 0.00692 (471/68022). AF 95% confidence interval is 0.00641. There are 2 homozygotes in gnomad4. There are 308 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3C2A	NM_002645.4	c.4782A>G	p.Pro1594=	synonymous_variant	32/33	ENST00000691414.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3C2A	ENST00000691414.1	c.4782A>G	p.Pro1594=	synonymous_variant	32/33		NM_002645.4	P1
PIK3C2A	ENST00000265970.11	c.4782A>G	p.Pro1594=	synonymous_variant	31/32	1		P1
PIK3C2A	ENST00000531428.1	n.1304A>G		non_coding_transcript_exon_variant	12/13	1

Frequencies

GnomAD3 genomes AF: 0.00416 AC: 634 AN: 152236 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.00434

Gnomad FIN AF: 0.00574

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00692

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00444 AC: 1115 AN: 250876 Hom.: 3 AF XY: 0.00476 AC XY: 645 AN XY: 135562

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.000872

Gnomad ASJ exome AF: 0.00338

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00352

Gnomad FIN exome AF: 0.00707

Gnomad NFE exome AF: 0.00657

Gnomad OTH exome AF: 0.00392

GnomAD4 exome AF: 0.00613 AC: 8965 AN: 1461402 Hom.: 48 Cov.: 31 AF XY: 0.00599 AC XY: 4354 AN XY: 726966

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.000784

Gnomad4 ASJ exome AF: 0.00394

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00382

Gnomad4 FIN exome AF: 0.00680

Gnomad4 NFE exome AF: 0.00704

Gnomad4 OTH exome AF: 0.00455

GnomAD4 genome AF: 0.00417 AC: 635 AN: 152354 Hom.: 2 Cov.: 32 AF XY: 0.00413 AC XY: 308 AN XY: 74504

Gnomad4 AFR AF: 0.00118

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.00455

Gnomad4 FIN AF: 0.00574

Gnomad4 NFE AF: 0.00692

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00569 Hom.: 1

Bravo AF: 0.00357

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00632

EpiControl AF: 0.00522

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	PIK3C2A: BP4, BP7, BS2 -

PIK3C2A-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 16, 2019

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
Cadd	Benign	5.8
Dann	Benign	0.49

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: rs61751351; hg19: chr11-17112977; COSMIC: COSV56402921;