Genetic Variant NM_001276277.3:c.1256C>T (chr5-103154708-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001276277.3(PPIP5K2):c.1256C>T(p.Ser419Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S419A) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Consequence

PPIP5K2
NM_001276277.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.39

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hearing loss, autosomal recessive 100
Inheritance: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

PPIP5K2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13683107).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001276277.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PPIP5K2	NM_001276277.3	MANE Select	c.1256C>T	p.Ser419Leu	missense	Exon 12 of 31	NP_001263206.1	O43314-1
PPIP5K2	NM_001281471.3		c.1256C>T	p.Ser419Leu	missense	Exon 12 of 33	NP_001268400.1	A0A087WZV0
PPIP5K2	NM_001345873.2		c.1256C>T	p.Ser419Leu	missense	Exon 12 of 31	NP_001332802.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PPIP5K2	ENST00000358359.8	TSL:1 MANE Select	c.1256C>T	p.Ser419Leu	missense	Exon 12 of 31	ENSP00000351126.3	O43314-1
PPIP5K2	ENST00000414217.5	TSL:1	c.1256C>T	p.Ser419Leu	missense	Exon 11 of 29	ENSP00000416016.1	O43314-2
PPIP5K2	ENST00000613674.4	TSL:2	c.1256C>T	p.Ser419Leu	missense	Exon 12 of 33	ENSP00000482907.1	A0A087WZV0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.013

Eigen

Benign

-0.22

Eigen_PC

Benign

0.0020

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.0070

MetaRNN

Benign

0.14

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

PhyloP100

4.4

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.88

REVEL

Benign

0.071

Sift

Benign

0.37

Sift4G

Benign

0.34

Polyphen

0.0

Vest4

0.35

MutPred

0.28

Loss of phosphorylation at S419 (P = 0.0229)

MVP

0.29

MPC

0.79

ClinPred

0.50

GERP RS

4.7

Varity_R

0.13

gMVP

0.58

Mutation Taster

=79/21

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.20

Position offset: 37

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over