NM_001276277.3:c.1213C>G

Variant names:

• chr5-103153930-C-G
• NM_001276277.3:c.1213C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001276277.3(PPIP5K2):​c.1213C>G​(p.Gln405Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000208 in 1,440,410 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PPIP5K2 NM_001276277.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.63
• Publications: 0 publications found

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

ACMG classification

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=0.21117392).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPIP5K2	NM_001276277.3	MANE Select	c.1213C>G	p.Gln405Glu	missense	Exon 11 of 31	NP_001263206.1	O43314-1
	PPIP5K2	NM_001281471.3		c.1213C>G	p.Gln405Glu	missense	Exon 11 of 33	NP_001268400.1	A0A087WZV0
	PPIP5K2	NM_001345873.2		c.1213C>G	p.Gln405Glu	missense	Exon 11 of 31	NP_001332802.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPIP5K2	ENST00000358359.8	TSL:1 MANE Select	c.1213C>G	p.Gln405Glu	missense	Exon 11 of 31	ENSP00000351126.3	O43314-1
	PPIP5K2	ENST00000414217.5	TSL:1	c.1213C>G	p.Gln405Glu	missense	Exon 10 of 29	ENSP00000416016.1	O43314-2
	PPIP5K2	ENST00000613674.4	TSL:2	c.1213C>G	p.Gln405Glu	missense	Exon 11 of 33	ENSP00000482907.1	A0A087WZV0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1440410 Hom.: 0 Cov.: 28 AF XY: 0.00000279 AC XY: 2 AN XY: 717196

African (AFR) AF: 0.00 AC: 0 AN: 32628

American (AMR) AF: 0.00 AC: 0 AN: 42496

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25716

East Asian (EAS) AF: 0.00 AC: 0 AN: 39150

South Asian (SAS) AF: 0.00 AC: 0 AN: 84052

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53026

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.00000273 AC: 3 AN: 1098068

Other (OTH) AF: 0.00 AC: 0 AN: 59576

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	24
DANN	Benign	0.84
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.093
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.40	N
PhyloP100		7.6
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.042
Sift	Benign	0.71	T
Sift4G	Benign	0.47	T
Polyphen		0.010	B
Vest4		0.47
MutPred		0.52		Loss of MoRF binding (P = 0.0338)
MVP		0.32
MPC		0.96
ClinPred		0.94	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.66
Mutation Taster		=56/44	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr5-102489634;