dbSNP rs10413655: PIK3R2:p.Ala548Val (chr19-18167213-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005027.4(PIK3R2):c.1643C>T(p.Ala548Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000949 in 1,611,792 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A548T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0023 ( 2 hom., cov: 31)

Exomes 𝑓: 0.00081 ( 7 hom. )

Consequence

PIK3R2
NM_005027.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.90

Publications

3 publications found

Variant links:

COSMIC-nc: COSV55849659

Genes affected

PIK3R2 (HGNC:8980): (phosphoinositide-3-kinase regulatory subunit 2) Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase that phosphorylates phosphatidylinositol and similar compounds, creating second messengers important in growth signaling pathways. PI3K functions as a heterodimer of a regulatory and a catalytic subunit. The protein encoded by this gene is a regulatory component of PI3K. Three transcript variants, one protein coding and the other two non-protein coding, have been found for this gene. [provided by RefSeq, Apr 2019]

PIK3R2 Gene-Disease associations (from GenCC):

megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Illumina, Genomics England PanelApp
overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PIK3R2 links:

ENSG00000268173 (HGNC:):

ENSG00000268173 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0069634914).

BP6

Variant 19-18167213-C-T is Benign according to our data. Variant chr19-18167213-C-T is described in ClinVar as Benign. ClinVar VariationId is 468318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00226 (344/152256) while in subpopulation AFR AF = 0.00585 (243/41556). AF 95% confidence interval is 0.00524. There are 2 homozygotes in GnomAd4. There are 153 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 344 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005027.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PIK3R2	NM_005027.4	MANE Select	c.1643C>T	p.Ala548Val	missense	Exon 13 of 16	NP_005018.2	O00459
PIK3R2	NR_073517.2		n.2247C>T		non_coding_transcript_exon	Exon 13 of 16
PIK3R2	NR_162071.1		n.1981C>T		non_coding_transcript_exon	Exon 12 of 15

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PIK3R2	ENST00000222254.13	TSL:1 MANE Select	c.1643C>T	p.Ala548Val	missense	Exon 13 of 16	ENSP00000222254.6	O00459
ENSG00000268173	ENST00000593731.1	TSL:2	n.1643C>T		non_coding_transcript_exon	Exon 13 of 25	ENSP00000471914.1
PIK3R2	ENST00000617130.6	TSL:1	n.*671C>T		non_coding_transcript_exon	Exon 12 of 15	ENSP00000477864.2	A0A7I2U3A3

Frequencies

GnomAD3 genomes

AF:

0.00225

AC:

343

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00584

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00210

Gnomad ASJ

AF:

0.0130

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00138

AC:

342

AN:

248238

AF XY:

0.00119

show subpopulations

Gnomad AFR exome

AF:

0.00507

Gnomad AMR exome

AF:

0.00158

Gnomad ASJ exome

AF:

0.0140

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000417

Gnomad OTH exome

AF:

0.00299

GnomAD4 exome

AF:

0.000812

AC:

1185

AN:

1459536

Hom.:

Cov.:

AF XY:

0.000763

AC XY:

554

AN XY:

726066

show subpopulations

African (AFR)

AF:

0.00637

AC:

212

AN:

33284

American (AMR)

AF:

0.00178

AC:

AN:

44414

Ashkenazi Jewish (ASJ)

AF:

0.0141

AC:

367

AN:

26094

East Asian (EAS)

AF:

0.00

AC:

AN:

39396

South Asian (SAS)

AF:

0.0000467

AC:

AN:

85734

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00226

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000346

AC:

384

AN:

1111128

Other (OTH)

AF:

0.00207

AC:

125

AN:

60326

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

114

171

228

285

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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:

0.00226

AC:

344

AN:

152256

Hom.:

Cov.:

AF XY:

0.00205

AC XY:

153

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00585

AC:

243

AN:

41556

American (AMR)

AF:

0.00209

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.0130

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000265

AC:

AN:

68012

Other (OTH)

AF:

0.00284

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

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:

0.00193

Hom.:

Bravo

AF:

0.00287

ESP6500AA

AF:

0.00590

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.00138

AC:

168

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000877

EpiControl

AF:

0.000775

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.62

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.58

M_CAP

Benign

0.0098

MetaRNN

Benign

0.0070

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

PhyloP100

1.9

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.4

REVEL

Benign

0.030

Sift

Benign

0.19

Sift4G

Benign

0.26

Polyphen

0.0

Vest4

0.12

MVP

0.23

MPC

0.83

ClinPred

0.0061

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.066

gMVP

0.12

Mutation Taster

=92/8

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over