NM_001276277.3:c.685C>T

Variant names:

• chr5-103147973-C-T
• rs782783744
• NM_001276277.3:c.685C>T

Variant summary

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

The NM_001276277.3(PPIP5K2):​c.685C>T​(p.Arg229*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000225 in 1,602,542 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: PPIP5K2 NM_001276277.3 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.11
• Publications: 2 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.685C>T	p.Arg229*	stop_gained	Exon 7 of 31	NP_001263206.1	O43314-1
	PPIP5K2	NM_001281471.3		c.685C>T	p.Arg229*	stop_gained	Exon 7 of 33	NP_001268400.1	A0A087WZV0
	PPIP5K2	NM_001345873.2		c.685C>T	p.Arg229*	stop_gained	Exon 7 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.685C>T	p.Arg229*	stop_gained	Exon 7 of 31	ENSP00000351126.3	O43314-1
	PPIP5K2	ENST00000414217.5	TSL:1	c.685C>T	p.Arg229*	stop_gained	Exon 6 of 29	ENSP00000416016.1	O43314-2
	PPIP5K2	ENST00000613674.4	TSL:2	c.685C>T	p.Arg229*	stop_gained	Exon 7 of 33	ENSP00000482907.1	A0A087WZV0

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151844 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000442

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000364 AC: 9 AN: 247422 AF XY: 0.0000598

Gnomad AFR exome AF: 0.0000623

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000110

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000445

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000227 AC: 33 AN: 1450698 Hom.: 0 Cov.: 28 AF XY: 0.0000277 AC XY: 20 AN XY: 721582

African (AFR) AF: 0.0000302 AC: 1 AN: 33094

American (AMR) AF: 0.00 AC: 0 AN: 44036

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25870

East Asian (EAS) AF: 0.0000763 AC: 3 AN: 39304

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 84014

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53178

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.0000244 AC: 27 AN: 1105534

Other (OTH) AF: 0.0000167 AC: 1 AN: 59932

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151844 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74152

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41390

American (AMR) AF: 0.00 AC: 0 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67856

Other (OTH) AF: 0.00 AC: 0 AN: 2082

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000096912), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000412 AC: 5

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hearing loss, autosomal recessive 100 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.84	D
PhyloP100		1.1
Vest4		0.55
GERP RS		4.5
Mutation Taster		=6/194	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs782783744; hg19: chr5-102483677; COSMIC: COSV58604589; COSMIC: COSV58604589;