rs36046591

Positions:

chr5-103201584-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2BP4_StrongBP6_ModerateBS1BS2

The NM_001276277.3(PPIP5K2):c.3682A>G(p.Ser1228Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0423 in 1,610,884 control chromosomes in the GnomAD database, including 1,709 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.031 ( 109 hom., cov: 32)

Exomes 𝑓: 0.043 ( 1600 hom. )

Consequence

PPIP5K2
NM_001276277.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 1.32

Variant links:

Genes affected

PPIP5K2 (HGNC:29035): (diphosphoinositol pentakisphosphate kinase 2) This gene encodes a member of the histidine acid phosphatase family of proteins. Despite containing a histidine acid phosphatase domain, the encoded protein functions as an inositol pyrophosphate kinase, and is thought to lack phosphatase activity. This kinase activity is the mechanism by which the encoded protein synthesizes high-energy inositol pyrophosphates, which act as signaling molecules that regulate cellular homeostasis and other processes. This gene may be associated with autism spectrum disorder in human patients. [provided by RefSeq, Sep 2016]

PPIP5K2 links:

PPIP5K2 (HGNC:):

PPIP5K2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PPIP5K2. . Gene score misZ 3.8022 (greater than the threshold 3.09). Trascript score misZ 4.0872 (greater than threshold 3.09). GenCC has associacion of gene with hearing loss, autosomal recessive 100, hearing loss, autosomal recessive.

BP4

Computational evidence support a benign effect (MetaRNN=0.0027911067).

BP6

Variant 5-103201584-A-G is Benign according to our data. Variant chr5-103201584-A-G is described in ClinVar as [Benign]. Clinvar id is 1174257.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0306 (4655/152242) while in subpopulation NFE AF= 0.0491 (3337/68010). AF 95% confidence interval is 0.0477. There are 109 homozygotes in gnomad4. There are 2230 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 109 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPIP5K2	NM_001276277.3 linkuse as main transcript	c.3682A>G	p.Ser1228Gly	missense_variant	31/31	ENST00000358359.8	NP_001263206.1	O43314-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPIP5K2	ENST00000358359.8 linkuse as main transcript	c.3682A>G	p.Ser1228Gly	missense_variant	31/31	1	NM_001276277.3	ENSP00000351126.3		O43314-1

Frequencies

GnomAD3 genomes

AF:

0.0306

AC:

4654

AN:

152126

Hom.:

109

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00818

Gnomad AMI

AF:

0.0384

Gnomad AMR

AF:

0.0147

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0130

Gnomad FIN

AF:

0.0567

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0490

Gnomad OTH

AF:

0.0220

GnomAD3 exomes

AF:

0.0303

AC:

7548

AN:

249112

Hom.:

180

AF XY:

0.0308

AC XY:

4143

AN XY:

134688

show subpopulations

Gnomad AFR exome

AF:

0.00818

Gnomad AMR exome

AF:

0.00993

Gnomad ASJ exome

AF:

0.00220

Gnomad EAS exome

AF:

0.0000548

Gnomad SAS exome

AF:

0.0155

Gnomad FIN exome

AF:

0.0611

Gnomad NFE exome

AF:

0.0451

Gnomad OTH exome

AF:

0.0312

GnomAD4 exome

AF:

0.0435

AC:

63432

AN:

1458642

Hom.:

1600

Cov.:

AF XY:

0.0424

AC XY:

30730

AN XY:

725604

show subpopulations

Gnomad4 AFR exome

AF:

0.00691

Gnomad4 AMR exome

AF:

0.0104

Gnomad4 ASJ exome

AF:

0.00288

Gnomad4 EAS exome

AF:

0.0000506

Gnomad4 SAS exome

AF:

0.0161

Gnomad4 FIN exome

AF:

0.0593

Gnomad4 NFE exome

AF:

0.0503

Gnomad4 OTH exome

AF:

0.0365

GnomAD4 genome

AF:

0.0306

AC:

4655

AN:

152242

Hom.:

109

Cov.:

AF XY:

0.0300

AC XY:

2230

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.00816

Gnomad4 AMR

AF:

0.0147

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0128

Gnomad4 FIN

AF:

0.0567

Gnomad4 NFE

AF:

0.0491

Gnomad4 OTH

AF:

0.0218

Alfa

AF:

0.0411

Hom.:

248

Bravo

AF:

0.0263

TwinsUK

AF:

0.0542

AC:

201

ALSPAC

AF:

0.0566

AC:

218

ESP6500AA

AF:

0.00772

AC:

ESP6500EA

AF:

0.0483

AC:

415

ExAC

AF:

0.0314

AC:

3817

Asia WGS

AF:

0.00347

AC:

AN:

3472

EpiCase

AF:

0.0374

EpiControl

AF:

0.0406

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

PPIP5K2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 11, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 05, 2021

This variant is associated with the following publications: (PMID: 31118516, 24464100, 27398621) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0083

.;T;T;.;T;.

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.058

LIST_S2

Benign

0.73

.;T;.;T;T;T

MetaRNN

Benign

0.0028

T;T;T;T;T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.35

N;N;.;N;.;N

REVEL

Benign

0.033

Sift

Benign

0.21

T;T;.;T;.;T

Sift4G

Benign

0.65

T;T;T;T;T;T

Polyphen

0.0

B;B;.;B;.;.

Vest4

0.051

MPC

0.10

ClinPred

0.0032

GERP RS

1.9

Varity_R

0.029

gMVP

0.31

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over