rs2298733

Variant names:

• chr4-105469577-A-C
• rs2298733
• NM_176869.3:c.157+4317T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_176869.3(PPA2):​c.157+4317T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.269 in 152,084 control chromosomes in the GnomAD database, including 7,677 homozygotes. 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: 𝑓 0.27 (7677 hom., cov: 32)
• Consequence: PPA2 NM_176869.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.185
• Publications: 6 publications found

Genes affected

PPA2 (HGNC:28883): (inorganic pyrophosphatase 2) The protein encoded by this gene is localized to the mitochondrion, is highly similar to members of the inorganic pyrophosphatase (PPase) family, and contains the signature sequence essential for the catalytic activity of PPase. PPases catalyze the hydrolysis of pyrophosphate to inorganic phosphate, which is important for the phosphate metabolism of cells. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

PPA2 Gene-Disease associations (from GenCC):

• sudden cardiac failure, infantile

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.533 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPA2	NM_176869.3	c.157+4317T>G		intron_variant	Intron 1 of 11	ENST00000341695.10	NP_789845.1
PPA2	NM_006903.4	c.157+4317T>G		intron_variant	Intron 1 of 10		NP_008834.3
PPA2	NM_176866.2	c.157+4317T>G		intron_variant	Intron 1 of 7		NP_789842.2
PPA2	NM_176867.3	c.157+4317T>G		intron_variant	Intron 1 of 5		NP_789843.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPA2	ENST00000341695.10	c.157+4317T>G		intron_variant	Intron 1 of 11	1	NM_176869.3	ENSP00000343885.5

Frequencies

GnomAD3 genomes AF: 0.268 AC: 40794 AN: 151966 Hom.: 7667 Cov.: 32

Gnomad AFR AF: 0.539

Gnomad AMI AF: 0.167

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.135

Gnomad EAS AF: 0.259

Gnomad SAS AF: 0.252

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.182

Gnomad NFE AF: 0.146

Gnomad OTH AF: 0.239

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.269 AC: 40852 AN: 152084 Hom.: 7677 Cov.: 32 AF XY: 0.270 AC XY: 20103 AN XY: 74374

African (AFR) AF: 0.539 AC: 22308 AN: 41426

American (AMR) AF: 0.190 AC: 2896 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.135 AC: 467 AN: 3470

East Asian (EAS) AF: 0.259 AC: 1339 AN: 5178

South Asian (SAS) AF: 0.251 AC: 1212 AN: 4822

European-Finnish (FIN) AF: 0.188 AC: 1989 AN: 10600

Middle Eastern (MID) AF: 0.168 AC: 49 AN: 292

European-Non Finnish (NFE) AF: 0.146 AC: 9934 AN: 67990

Other (OTH) AF: 0.240 AC: 506 AN: 2112

Alfa AF: 0.186 Hom.: 11241

Bravo AF: 0.283

Asia WGS AF: 0.256 AC: 889 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.6
DANN	Benign	0.67
PhyloP100		-0.18
Mutation Taster		=100/0	polymorphism (auto)

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: rs2298733; hg19: chr4-106390734;