5-103138467-A-G

Variant names:

• chr5-103138467-A-G
• rs781988239
• NM_001276277.3:c.485A>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.485A>G​(p.Lys162Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,440,264 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K162T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PPIP5K2 NM_001276277.3 missense, splice_region
• Scores: Splicing: ADA: 0.1095
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.81
• 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=0.22088072).

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.485A>G	p.Lys162Arg	missense splice_region	Exon 5 of 31	NP_001263206.1	O43314-1
	PPIP5K2	NM_001281471.3		c.485A>G	p.Lys162Arg	missense splice_region	Exon 5 of 33	NP_001268400.1	A0A087WZV0
	PPIP5K2	NM_001345873.2		c.485A>G	p.Lys162Arg	missense splice_region	Exon 5 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.485A>G	p.Lys162Arg	missense splice_region	Exon 5 of 31	ENSP00000351126.3	O43314-1
	PPIP5K2	ENST00000414217.5	TSL:1	c.485A>G	p.Lys162Arg	missense splice_region	Exon 4 of 29	ENSP00000416016.1	O43314-2
	PPIP5K2	ENST00000613674.4	TSL:2	c.485A>G	p.Lys162Arg	missense splice_region	Exon 5 of 33	ENSP00000482907.1	A0A087WZV0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1440264 Hom.: 0 Cov.: 28 AF XY: 0.00000139 AC XY: 1 AN XY: 717626

African (AFR) AF: 0.00 AC: 0 AN: 32834

American (AMR) AF: 0.00 AC: 0 AN: 43786

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25920

East Asian (EAS) AF: 0.00 AC: 0 AN: 39224

South Asian (SAS) AF: 0.00 AC: 0 AN: 85094

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53328

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.00000183 AC: 2 AN: 1094738

Other (OTH) AF: 0.00 AC: 0 AN: 59618

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.50
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.039	T
Eigen	Benign	0.016
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		8.8
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.077
Sift	Benign	0.094	T
Sift4G	Benign	0.18	T
Polyphen		0.0010	B
Vest4		0.14
MutPred		0.32		Loss of ubiquitination at K162 (P = 0.0074)
MVP		0.37
MPC		0.73
ClinPred		0.74	D
GERP RS		4.9
Varity_R		0.45
gMVP		0.43
Mutation Taster		=62/38	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.11
dbscSNV1_RF	Benign	0.31
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.21		Position offset: 22

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

Other links and lift over

dbSNP: rs781988239; hg19: chr5-102474171;