chr11-17089924-C-A

Variant names:

• chr11-17089924-C-A
• rs376168387
• NM_002645.4:c.4879-4G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002645.4(PIK3C2A):​c.4879-4G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000797 in 1,380,334 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000080 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PIK3C2A NM_002645.4 splice_region, intron
• Scores: Splicing: ADA: 0.000008348
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.17
• Publications: 0 publications found

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]

PIK3C2A Gene-Disease associations (from GenCC):

• oculocerebrodental syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002645.4. 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
	PIK3C2A	NM_002645.4	MANE Select	c.4879-4G>T		splice_region intron	N/A	NP_002636.2	L7RRS0
	PIK3C2A	NM_001321378.2		c.4879-4G>T		splice_region intron	N/A	NP_001308307.1	O00443-1
	PIK3C2A	NM_001386870.1		c.4711-4G>T		splice_region intron	N/A	NP_001373799.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3C2A	ENST00000691414.1	MANE Select	c.4879-4G>T		splice_region intron	N/A	ENSP00000509400.1	O00443-1
	PIK3C2A	ENST00000265970.11	TSL:1	c.4879-4G>T		splice_region intron	N/A	ENSP00000265970.6	O00443-1
	PIK3C2A	ENST00000531428.1	TSL:1	n.1400+1410G>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 151954 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD2 exomes AF: 0.0000193 AC: 4 AN: 206874 AF XY: 0.0000177

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000936

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000200

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000797 AC: 11 AN: 1380334 Hom.: 0 Cov.: 27 AF XY: 0.00000587 AC XY: 4 AN XY: 681070

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30122

American (AMR) AF: 0.000191 AC: 6 AN: 31412

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23156

East Asian (EAS) AF: 0.00 AC: 0 AN: 38026

South Asian (SAS) AF: 0.0000131 AC: 1 AN: 76524

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51872

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5416

European-Non Finnish (NFE) AF: 0.00000375 AC: 4 AN: 1067264

Other (OTH) AF: 0.00 AC: 0 AN: 56542

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 151954 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74202

African (AFR) AF: 0.00 AC: 0 AN: 41358

American (AMR) AF: 0.00 AC: 0 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10544

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67992

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000461 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.69
DANN	Benign	0.72
PhyloP100		-2.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000083
dbscSNV1_RF	Benign	0.0020
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: rs376168387; hg19: chr11-17111471;