Genetic Variant NM_002645.4:c.4879-4G>A (chr11-17089924-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 2P and 10B. PM2BP4_StrongBP6_ModerateBS1

The NM_002645.4(PIK3C2A):c.4879-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000215 in 1,532,330 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. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

PIK3C2A
NM_002645.4 splice_region, intron

Scores

Splicing: ADA: 0.000007886

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.17

Publications

0 publications found

Variant links:

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

PIK3C2A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 11-17089924-C-T is Benign according to our data. Variant chr11-17089924-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2169043.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0000526 (8/151958) while in subpopulation NFE AF = 0.0000735 (5/67994). AF 95% confidence interval is 0.0000285. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PIK3C2A	NM_002645.4	MANE Select	c.4879-4G>A	splice_region intron	N/A	NP_002636.2	L7RRS0
PIK3C2A	NM_001321378.2		c.4879-4G>A	splice_region intron	N/A	NP_001308307.1	O00443-1
PIK3C2A	NM_001386870.1		c.4711-4G>A	splice_region intron	N/A	NP_001373799.1

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

151958

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000387

AC:

AN:

206874

AF XY:

0.00000887

show subpopulations

Gnomad AFR exome

AF:

0.000134

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000599

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000181

AC:

AN:

1380372

Hom.:

Cov.:

AF XY:

0.0000176

AC XY:

AN XY:

681088

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30128

American (AMR)

AF:

0.00

AC:

AN:

31428

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23158

East Asian (EAS)

AF:

0.00

AC:

AN:

38026

South Asian (SAS)

AF:

0.0000261

AC:

AN:

76524

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51872

Middle Eastern (MID)

AF:

0.000185

AC:

AN:

5416

European-Non Finnish (NFE)

AF:

0.0000178

AC:

AN:

1067278

Other (OTH)

AF:

0.0000531

AC:

AN:

56542

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000526

AC:

AN:

151958

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74204

show subpopulations

African (AFR)

AF:

0.0000725

AC:

AN:

41358

American (AMR)

AF:

0.00

AC:

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10546

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

67994

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000921

Hom.:

Bravo

AF:

0.0000567

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.88

(source)

DANN

Benign

0.74

PhyloP100

-2.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0000079

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over