dbSNP rs148245146: PIK3R2:c.-18C>T (chr19-18155862-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.-18C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000394 in 1,531,578 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00038 ( 3 hom. )

Consequence

PIK3R2
NM_005027.4 5_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.123

Publications

1 publications found

Variant links:

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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Illumina, G2P
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 (BayesDel_noAF=-0.64).

BP6

Variant 19-18155862-C-T is Benign according to our data. Variant chr19-18155862-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1219807.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000505 (77/152352) while in subpopulation EAS AF = 0.0129 (67/5186). AF 95% confidence interval is 0.0104. There are 0 homozygotes in GnomAd4. There are 41 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 77 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	Effect	Exon Rank	Protein	UniProt
PIK3R2	NM_005027.4	MANE Select	c.-18C>T	5_prime_UTR	Exon 2 of 16	NP_005018.2	O00459
PIK3R2	NR_073517.2		n.538C>T	non_coding_transcript_exon	Exon 2 of 16
PIK3R2	NR_162071.1		n.538C>T	non_coding_transcript_exon	Exon 2 of 15

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PIK3R2	ENST00000222254.13	TSL:1 MANE Select	c.-18C>T	5_prime_UTR	Exon 2 of 16	ENSP00000222254.6	O00459
ENSG00000268173	ENST00000593731.1	TSL:2	n.-18C>T	non_coding_transcript_exon	Exon 2 of 25	ENSP00000471914.1
PIK3R2	ENST00000617130.6	TSL:1	n.-18C>T	non_coding_transcript_exon	Exon 2 of 15	ENSP00000477864.2	A0A7I2U3A3

Frequencies

GnomAD3 genomes

AF:

0.000506

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0129

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000957

AC:

131

AN:

136902

AF XY:

0.000873

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000445

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0120

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000195

Gnomad OTH exome

AF:

0.000253

GnomAD4 exome

AF:

0.000381

AC:

526

AN:

1379226

Hom.:

Cov.:

AF XY:

0.000377

AC XY:

256

AN XY:

678950

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30018

American (AMR)

AF:

0.00

AC:

AN:

33618

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24060

East Asian (EAS)

AF:

0.0114

AC:

395

AN:

34796

South Asian (SAS)

AF:

0.000689

AC:

AN:

76946

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47506

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5612

European-Non Finnish (NFE)

AF:

0.0000617

AC:

AN:

1069490

Other (OTH)

AF:

0.000210

AC:

AN:

57180

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

130

163

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.000505

AC:

AN:

152352

Hom.:

Cov.:

AF XY:

0.000550

AC XY:

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.0000240

AC:

AN:

41590

American (AMR)

AF:

0.0000654

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.0129

AC:

AN:

5186

South Asian (SAS)

AF:

0.000827

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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:

0.0000855

Hom.:

Bravo

AF:

0.000737

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Benign

0.92

PhyloP100

0.12

Mutation Taster

=300/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over