Genetic Variant PIK3R6:p.Ile534Val (chr17-8823413-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001010855.4(PIK3R6):c.1600A>G(p.Ile534Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000838 in 1,552,170 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000087 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0000083 ( 0 hom. )

Consequence

PIK3R6
NM_001010855.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.07

Publications

0 publications found

Variant links:

Genes affected

PIK3R6 (HGNC:27101): (phosphoinositide-3-kinase regulatory subunit 6) Phosphoinositide 3-kinase gamma is a lipid kinase that produces the lipid second messenger phosphatidylinositol 3,4,5-trisphosphate. The kinase is composed of a catalytic subunit and one of several regulatory subunits, and is chiefly activated by G protein-coupled receptors. This gene encodes a regulatory subunit, and is distantly related to the phosphoinositide-3-kinase, regulatory subunit 5 gene which is located adjacent to this gene on chromosome 7. The orthologous protein in the mouse binds to both the catalytic subunit and to G(beta/gamma), and mediates activation of the kinase subunit downstream of G protein-coupled receptors. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

PIK3R6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08560243).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001010855.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PIK3R6	NM_001010855.4	MANE Select	c.1600A>G	p.Ile534Val	missense	Exon 14 of 20	NP_001010855.1	Q5UE93
PIK3R6	NM_001290211.1		c.1192A>G	p.Ile398Val	missense	Exon 14 of 20	NP_001277140.1	B3KRK9
PIK3R6	NR_110865.1		n.1935A>G		non_coding_transcript_exon	Exon 13 of 20

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PIK3R6	ENST00000619866.5	TSL:5 MANE Select	c.1600A>G	p.Ile534Val	missense	Exon 14 of 20	ENSP00000480157.1	Q5UE93
PIK3R6	ENST00000907451.1		c.1600A>G	p.Ile534Val	missense	Exon 14 of 20	ENSP00000577510.1
PIK3R6	ENST00000907452.1		c.1585A>G	p.Ile529Val	missense	Exon 14 of 20	ENSP00000577511.1

Frequencies

GnomAD3 genomes

AF:

0.00000870

AC:

AN:

114938

Hom.:

Cov.:

show subpopulations

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:

0.0000193

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000121

AC:

AN:

248186

AF XY:

0.0000223

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000266

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000835

AC:

AN:

1437232

Hom.:

Cov.:

AF XY:

0.00000699

AC XY:

AN XY:

714926

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32880

American (AMR)

AF:

0.00

AC:

AN:

43674

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25646

East Asian (EAS)

AF:

0.00

AC:

AN:

38726

South Asian (SAS)

AF:

0.00

AC:

AN:

82624

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5690

European-Non Finnish (NFE)

AF:

0.0000109

AC:

AN:

1096152

Other (OTH)

AF:

0.00

AC:

AN:

59246

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

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:

0.00000870

AC:

AN:

114938

Hom.:

Cov.:

AF XY:

0.0000177

AC XY:

AN XY:

56390

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

30098

American (AMR)

AF:

0.00

AC:

AN:

11318

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2676

East Asian (EAS)

AF:

0.00

AC:

AN:

3986

South Asian (SAS)

AF:

0.00

AC:

AN:

3688

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9008

Middle Eastern (MID)

AF:

0.00

AC:

AN:

204

European-Non Finnish (NFE)

AF:

0.0000193

AC:

AN:

51768

Other (OTH)

AF:

0.00

AC:

AN:

1518

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

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:

0.0000202

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000121

AC:

ExAC

AF:

0.00000827

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.093

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.12

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.68

M_CAP

Benign

0.0032

MetaRNN

Benign

0.086

PhyloP100

1.1

PrimateAI

Benign

0.36

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.17

MVP

0.085

GERP RS

-0.25

Varity_R

0.081

gMVP

0.21

Mutation Taster

=97/3

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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