rs114517746

Variant names:

• chr5-103136793-C-T
• rs114517746
• NM_001276277.3:c.372C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_001276277.3(PPIP5K2):​c.372C>T​(p.Asp124Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0023 in 1,613,514 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.012 (35 hom., cov: 31)
  • Exomes 𝑓: 0.0013 (32 hom.)
• Consequence: PPIP5K2 NM_001276277.3 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.17
• Publications: 1 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 5-103136793-C-T is Benign according to our data. Variant chr5-103136793-C-T is described in ClinVar as Benign. ClinVar VariationId is 3038316.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=2.17 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0123 (1868/152250) while in subpopulation AFR AF = 0.0435 (1808/41536). AF 95% confidence interval is 0.0419. There are 35 homozygotes in GnomAd4. There are 891 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 35 AR,Unknown gene

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.372C>T	p.Asp124Asp	synonymous	Exon 4 of 31	NP_001263206.1	O43314-1
	PPIP5K2	NM_001281471.3		c.372C>T	p.Asp124Asp	synonymous	Exon 4 of 33	NP_001268400.1	A0A087WZV0
	PPIP5K2	NM_001345873.2		c.372C>T	p.Asp124Asp	synonymous	Exon 4 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.372C>T	p.Asp124Asp	synonymous	Exon 4 of 31	ENSP00000351126.3	O43314-1
	PPIP5K2	ENST00000414217.5	TSL:1	c.372C>T	p.Asp124Asp	synonymous	Exon 3 of 29	ENSP00000416016.1	O43314-2
	PPIP5K2	ENST00000613674.4	TSL:2	c.372C>T	p.Asp124Asp	synonymous	Exon 4 of 33	ENSP00000482907.1	A0A087WZV0

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1859 AN: 152132 Hom.: 35 Cov.: 31

Gnomad AFR AF: 0.0434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00298 AC: 749 AN: 251388 AF XY: 0.00199

Gnomad AFR exome AF: 0.0417

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.00127 AC: 1851 AN: 1461264 Hom.: 32 Cov.: 30 AF XY: 0.00108 AC XY: 786 AN XY: 726982

African (AFR) AF: 0.0445 AC: 1489 AN: 33444

American (AMR) AF: 0.00179 AC: 80 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39636

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5764

European-Non Finnish (NFE) AF: 0.0000657 AC: 73 AN: 1111588

Other (OTH) AF: 0.00293 AC: 177 AN: 60368

GnomAD4 genome AF: 0.0123 AC: 1868 AN: 152250 Hom.: 35 Cov.: 31 AF XY: 0.0120 AC XY: 891 AN XY: 74436

African (AFR) AF: 0.0435 AC: 1808 AN: 41536

American (AMR) AF: 0.00262 AC: 40 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68024

Other (OTH) AF: 0.00663 AC: 14 AN: 2112

Alfa AF: 0.00542 Hom.: 6

Bravo AF: 0.0139

Asia WGS AF: 0.00318 AC: 11 AN: 3476

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	PPIP5K2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	11
DANN	Benign	0.64
PhyloP100		2.2
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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

dbSNP: rs114517746; hg19: chr5-102472497;