4-105396272-C-G

Variant names:

• chr4-105396272-C-G
• rs13787
• NM_176869.3:c.846G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_176869.3(PPA2):​c.846G>C​(p.Lys282Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.45 in 1,585,366 control chromosomes in the GnomAD database, including 167,646 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (12583 hom., cov: 32)
  • Exomes 𝑓: 0.46 (155063 hom.)
• Consequence: PPA2 NM_176869.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.173
• Publications: 36 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0045214E-5).
• BP6: Variant 4-105396272-C-G is Benign according to our data. Variant chr4-105396272-C-G is described in ClinVar as Benign. ClinVar VariationId is 1270616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.662 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_176869.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPA2	NM_176869.3	MANE Select	c.846G>C	p.Lys282Asn	missense	Exon 9 of 12	NP_789845.1
	PPA2	NM_006903.4		c.759G>C	p.Lys253Asn	missense	Exon 8 of 11	NP_008834.3
	PPA2	NM_176866.2		c.540G>C	p.Lys180Asn	missense	Exon 5 of 8	NP_789842.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPA2	ENST00000341695.10	TSL:1 MANE Select	c.846G>C	p.Lys282Asn	missense	Exon 9 of 12	ENSP00000343885.5
	PPA2	ENST00000348706.9	TSL:1	c.759G>C	p.Lys253Asn	missense	Exon 8 of 11	ENSP00000313061.8
	PPA2	ENST00000432483.6	TSL:1	c.540G>C	p.Lys180Asn	missense	Exon 5 of 8	ENSP00000389957.2

Frequencies

GnomAD3 genomes AF: 0.374 AC: 56792 AN: 151874 Hom.: 12573 Cov.: 32

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.441

Gnomad AMR AF: 0.484

Gnomad ASJ AF: 0.422

Gnomad EAS AF: 0.680

Gnomad SAS AF: 0.521

Gnomad FIN AF: 0.412

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.457

Gnomad OTH AF: 0.381

GnomAD2 exomes AF: 0.448 AC: 105583 AN: 235754 AF XY: 0.452

Gnomad AFR exome AF: 0.112

Gnomad AMR exome AF: 0.515

Gnomad ASJ exome AF: 0.425

Gnomad EAS exome AF: 0.652

Gnomad FIN exome AF: 0.421

Gnomad NFE exome AF: 0.445

Gnomad OTH exome AF: 0.434

GnomAD4 exome AF: 0.458 AC: 656349 AN: 1433374 Hom.: 155063 Cov.: 30 AF XY: 0.459 AC XY: 327484 AN XY: 713006

African (AFR) AF: 0.109 AC: 3611 AN: 33048

American (AMR) AF: 0.513 AC: 21242 AN: 41386

Ashkenazi Jewish (ASJ) AF: 0.428 AC: 10935 AN: 25538

East Asian (EAS) AF: 0.708 AC: 27284 AN: 38540

South Asian (SAS) AF: 0.494 AC: 40135 AN: 81206

European-Finnish (FIN) AF: 0.417 AC: 22020 AN: 52798

Middle Eastern (MID) AF: 0.401 AC: 2162 AN: 5392

European-Non Finnish (NFE) AF: 0.459 AC: 502926 AN: 1096264

Other (OTH) AF: 0.440 AC: 26034 AN: 59202

GnomAD4 genome AF: 0.374 AC: 56811 AN: 151992 Hom.: 12583 Cov.: 32 AF XY: 0.376 AC XY: 27944 AN XY: 74262

African (AFR) AF: 0.126 AC: 5210 AN: 41510

American (AMR) AF: 0.484 AC: 7381 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.422 AC: 1465 AN: 3468

East Asian (EAS) AF: 0.681 AC: 3519 AN: 5170

South Asian (SAS) AF: 0.520 AC: 2507 AN: 4820

European-Finnish (FIN) AF: 0.412 AC: 4343 AN: 10538

Middle Eastern (MID) AF: 0.390 AC: 114 AN: 292

European-Non Finnish (NFE) AF: 0.457 AC: 31057 AN: 67920

Other (OTH) AF: 0.385 AC: 813 AN: 2110

Alfa AF: 0.440 Hom.: 11420

Bravo AF: 0.367

TwinsUK AF: 0.468 AC: 1736

ALSPAC AF: 0.462 AC: 1781

ESP6500AA AF: 0.133 AC: 585

ESP6500EA AF: 0.457 AC: 3925

ExAC AF: 0.454 AC: 55093

Asia WGS AF: 0.582 AC: 2019 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 06, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Sudden cardiac failure, infantile Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.000010	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		-0.17
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.099
Sift	Benign	0.069	T
Sift4G	Benign	0.16	T
Polyphen		0.038	B
Vest4		0.066
MutPred		0.18		Loss of methylation at K282 (P = 0.0027)
MPC		0.19
ClinPred		0.037	T
GERP RS		0.10
Varity_R		0.20
gMVP		0.66
Mutation Taster		=97/3	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: rs13787; hg19: chr4-106317429; COSMIC: COSV58995765; COSMIC: COSV58995765;