chr4-105396272-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.37 ( 12583 hom., cov: 32)

Exomes 𝑓: 0.46 ( 155063 hom. )

Consequence

PPA2
NM_176869.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.173

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 id is 1270616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-105396272-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.662 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPA2	NM_176869.3 link	c.846G>C	p.Lys282Asn	missense_variant	Exon 9 of 12	ENST00000341695.10	NP_789845.1	Q9H2U2-1
PPA2	NM_006903.4 link	c.759G>C	p.Lys253Asn	missense_variant	Exon 8 of 11		NP_008834.3	Q9H2U2-3
PPA2	NM_176866.2 link	c.540G>C	p.Lys180Asn	missense_variant	Exon 5 of 8		NP_789842.2	Q9H2U2-6
PPA2	NM_176867.3 link	c.348G>C	p.Lys116Asn	missense_variant	Exon 3 of 6		NP_789843.2	Q9H2U2-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPA2	ENST00000341695.10 link	c.846G>C	p.Lys282Asn	missense_variant	Exon 9 of 12	1	NM_176869.3	ENSP00000343885.5		Q9H2U2-1

Frequencies

GnomAD3 genomes

AF:

0.374

AC:

56792

AN:

151874

Hom.:

12573

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.459

AC XY:

327484

AN XY:

713006

show subpopulations

Gnomad4 AFR exome

AF:

0.109

AC:

3611

AN:

33048

Gnomad4 AMR exome

AF:

0.513

AC:

21242

AN:

41386

Gnomad4 ASJ exome

AF:

0.428

AC:

10935

AN:

25538

Gnomad4 EAS exome

AF:

0.708

AC:

27284

AN:

38540

Gnomad4 SAS exome

AF:

0.494

AC:

40135

AN:

81206

Gnomad4 FIN exome

AF:

0.417

AC:

22020

AN:

52798

Gnomad4 NFE exome

AF:

0.459

AC:

502926

AN:

1096264

Gnomad4 Remaining exome

AF:

0.440

AC:

26034

AN:

59202

Heterozygous variant carriers

15750

31500

47251

63001

78751

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

15124

30248

45372

60496

75620

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.374

AC:

56811

AN:

151992

Hom.:

12583

Cov.:

AF XY:

0.376

AC XY:

27944

AN XY:

74262

show subpopulations

Gnomad4 AFR

AF:

0.126

AC:

0.125512

AN:

0.125512

Gnomad4 AMR

AF:

0.484

AC:

0.483937

AN:

0.483937

Gnomad4 ASJ

AF:

0.422

AC:

0.422434

AN:

0.422434

Gnomad4 EAS

AF:

0.681

AC:

0.680658

AN:

0.680658

Gnomad4 SAS

AF:

0.520

AC:

0.520124

AN:

0.520124

Gnomad4 FIN

AF:

0.412

AC:

0.412128

AN:

0.412128

Gnomad4 NFE

AF:

0.457

AC:

0.457259

AN:

0.457259

Gnomad4 OTH

AF:

0.385

AC:

0.385308

AN:

0.385308

Heterozygous variant carriers

1657

3315

4972

6630

8287

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

554

1108

1662

2216

2770

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

LINK: link

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

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Sep 06, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

T;.;.;.

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.66

T;T;T;T

MetaRNN

Benign

0.000010

T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.3

M;.;.;.

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-2.6

D;D;D;D

REVEL

Benign

0.099

Sift

Benign

0.069

T;T;T;T

Sift4G

Benign

0.16

T;T;D;T

Polyphen

0.038

B;B;P;.

Vest4

0.066

MutPred

0.18

Loss of methylation at K282 (P = 0.0027);.;.;.;

MPC

0.19

ClinPred

0.037

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over