5-103154707-T-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_001276277.3(PPIP5K2):c.1255T>G(p.Ser419Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00978 in 1,579,160 control chromosomes in the GnomAD database, including 106 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (7 hom., cov: 32)
  • Exomes 𝑓: 0.010 (99 hom.)
• Consequence: PPIP5K2 NM_001276277.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.35

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, PPIP5K2
• BP4: Computational evidence support a benign effect (MetaRNN=0.005351007).
• BP6: Variant 5-103154707-T-G is Benign according to our data. Variant chr5-103154707-T-G is described in ClinVar as [Benign]. Clinvar id is 2655626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPIP5K2	NM_001276277.3	c.1255T>G	p.Ser419Ala	missense_variant	12/31	ENST00000358359.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPIP5K2	ENST00000358359.8	c.1255T>G	p.Ser419Ala	missense_variant	12/31	1	NM_001276277.3	P4

Frequencies

GnomAD3 genomes AF: 0.00652 AC: 991 AN: 152066 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.0407

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00415

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0113

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00681 AC: 1638 AN: 240504 Hom.: 8 AF XY: 0.00663 AC XY: 861 AN XY: 129902

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.00279

Gnomad ASJ exome AF: 0.00395

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000361

Gnomad FIN exome AF: 0.00466

Gnomad NFE exome AF: 0.0122

Gnomad OTH exome AF: 0.00515

GnomAD4 exome AF: 0.0101 AC: 14450 AN: 1426976 Hom.: 99 Cov.: 29 AF XY: 0.00987 AC XY: 7008 AN XY: 709974

Gnomad4 AFR exome AF: 0.00164

Gnomad4 AMR exome AF: 0.00284

Gnomad4 ASJ exome AF: 0.00443

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000643

Gnomad4 FIN exome AF: 0.00601

Gnomad4 NFE exome AF: 0.0123

Gnomad4 OTH exome AF: 0.00725

GnomAD4 genome AF: 0.00651 AC: 991 AN: 152184 Hom.: 7 Cov.: 32 AF XY: 0.00568 AC XY: 423 AN XY: 74410

Gnomad4 AFR AF: 0.00173

Gnomad4 AMR AF: 0.00262

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00415

Gnomad4 NFE AF: 0.0113

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.0100 Hom.: 6

Bravo AF: 0.00614

TwinsUK AF: 0.0121 AC: 45

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.00160 AC: 7

ESP6500EA AF: 0.0116 AC: 99

ExAC AF: 0.00761 AC: 923

Asia WGS AF: 0.000290 AC: 1 AN: 3460

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PPIP5K2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 18, 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

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2022

PPIP5K2: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.61
Cadd	Uncertain	23
Dann	Benign	0.87
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.90	D
MetaRNN	Benign	0.0054	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L;.;L;.;L;.
MutationTaster	Benign	0.69	N;N;N
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.83	N;N;N;.;N;.
REVEL	Benign	0.027
Sift	Benign	0.78	T;T;T;.;T;.
Sift4G	Benign	0.76	T;T;T;T;T;T
Polyphen		0.0	B;B;B;.;B;.
Vest4		0.31
MVP		0.11
MPC		0.74
ClinPred		0.0097	T
GERP RS		3.4
Varity_R		0.050
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs35671301; hg19: chr5-102490411;