NM_001142633.3:c.2557C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001142633.3(PIK3R5):c.2557C>T(p.Pro853Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00345 in 1,613,940 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0027 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0035 ( 16 hom. )

Consequence

PIK3R5
NM_001142633.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: -0.833

Publications

3 publications found

Variant links:

Genes affected

PIK3R5 (HGNC:30035): (phosphoinositide-3-kinase regulatory subunit 5) Phosphatidylinositol 3-kinases (PI3Ks) phosphorylate the inositol ring of phosphatidylinositol at the 3-prime position, and play important roles in cell growth, proliferation, differentiation, motility, survival and intracellular trafficking. The PI3Ks are divided into three classes: I, II and III, and only the class I PI3Ks are involved in oncogenesis. This gene encodes the 101 kD regulatory subunit of the class I PI3K gamma complex, which is a dimeric enzyme, consisting of a 110 kD catalytic subunit gamma and a regulatory subunit of either 55, 87 or 101 kD. This protein recruits the catalytic subunit from the cytosol to the plasma membrane through high-affinity interaction with G-beta-gamma proteins. Multiple alternatively spliced transcript variants encoding two distinct isoforms have been found. [provided by RefSeq, Oct 2011]

PIK3R5 Gene-Disease associations (from GenCC):

spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PIK3R5 links:

LOC124903919 (HGNC:):

LOC124903919 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0077055395).

BP6

Variant 17-8880725-G-A is Benign according to our data. Variant chr17-8880725-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211906.

BS2

High Homozygotes in GnomAdExome4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3R5	NM_001142633.3 link	c.2557C>T	p.Pro853Ser	missense_variant	Exon 19 of 19	ENST00000447110.6	NP_001136105.1	Q8WYR1-1L7RT34

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3R5	ENST00000447110.6 link	c.2557C>T	p.Pro853Ser	missense_variant	Exon 19 of 19	5	NM_001142633.3	ENSP00000392812.1		Q8WYR1-1

Frequencies

GnomAD3 genomes

AF:

0.00275

AC:

418

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00327

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.00508

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00370

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.00297

AC:

741

AN:

249854

AF XY:

0.00308

show subpopulations

Gnomad AFR exome

AF:

0.000616

Gnomad AMR exome

AF:

0.00281

Gnomad ASJ exome

AF:

0.00109

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00456

Gnomad NFE exome

AF:

0.00407

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.00352

AC:

5144

AN:

1461636

Hom.:

Cov.:

AF XY:

0.00353

AC XY:

2568

AN XY:

727106

show subpopulations

African (AFR)

AF:

0.000657

AC:

AN:

33478

American (AMR)

AF:

0.00291

AC:

130

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.000995

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00194

AC:

167

AN:

86234

European-Finnish (FIN)

AF:

0.00348

AC:

186

AN:

53384

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00399

AC:

4431

AN:

1111880

Other (OTH)

AF:

0.00300

AC:

181

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

271

543

814

1086

1357

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

168

336

504

672

840

<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:

0.00274

AC:

418

AN:

152304

Hom.:

Cov.:

AF XY:

0.00306

AC XY:

228

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.000963

AC:

AN:

41552

American (AMR)

AF:

0.00327

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00248

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00508

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00370

AC:

252

AN:

68024

Other (OTH)

AF:

0.00379

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

120

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:

0.00342

Hom.:

Bravo

AF:

0.00252

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00488

AC:

ExAC

AF:

0.00280

AC:

340

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00365

EpiControl

AF:

0.00421

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 06, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PIK3R5: BP4, BS2 -

Ataxia with oculomotor apraxia type 3

Uncertain:1

Feb 26, 2018

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not specified

Benign:1

Jul 03, 2019

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.47

CADD

Benign

0.028

(source)

DANN

Benign

0.38

DEOGEN2

Benign

0.11

T;.;.;.;T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.43

T;.;.;T;.;T

M_CAP

Benign

0.033

MetaRNN

Benign

0.0077

T;T;T;T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.18

N;.;.;.;N;.

PhyloP100

-0.83

PrimateAI

Benign

0.27

PROVEAN

Benign

0.71

N;.;.;.;.;.

REVEL

Benign

0.10

Sift

Benign

0.50

T;.;.;.;.;.

Sift4G

Benign

0.45

T;T;T;T;T;T

Polyphen

0.0

B;.;.;.;B;.

Vest4

0.029

MVP

0.18

MPC

0.48

ClinPred

0.00090

GERP RS

-5.6

Varity_R

0.017

gMVP

0.16

Mutation Taster

=100/0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over