5-103154708-C-T

Position:

• chr5-103154708-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPIP5K2 NM_001276277.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.39

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.13683107).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPIP5K2	NM_001276277.3	c.1256C>T	p.Ser419Leu	missense_variant	12/31	ENST00000358359.8	NP_001263206.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPIP5K2	ENST00000358359.8	c.1256C>T	p.Ser419Leu	missense_variant	12/31	1	NM_001276277.3	ENSP00000351126.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 10, 2024

The c.1256C>T (p.S419L) alteration is located in exon 11 (coding exon 11) of the PPIP5K2 gene. This alteration results from a C to T substitution at nucleotide position 1256, causing the serine (S) at amino acid position 419 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.013	.;.;T;T;.;T
Eigen	Benign	-0.22
Eigen_PC	Benign	0.0020
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	.;D;D;.;D;D
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.14	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;.;L;.;L;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.88	N;N;N;.;N;.
REVEL	Benign	0.071
Sift	Benign	0.37	T;T;T;.;T;.
Sift4G	Benign	0.34	T;T;T;T;T;T
Polyphen		0.0	B;B;B;.;B;.
Vest4		0.35
MutPred		0.28		Loss of phosphorylation at S419 (P = 0.0229);.;Loss of phosphorylation at S419 (P = 0.0229);Loss of phosphorylation at S419 (P = 0.0229);Loss of phosphorylation at S419 (P = 0.0229);Loss of phosphorylation at S419 (P = 0.0229);
MVP		0.29
MPC		0.79
ClinPred		0.50	D
GERP RS		4.7
Varity_R		0.13
gMVP		0.58

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-102490412;