rs138215926

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP5_Very_Strong

The NM_176869.3(PPA2):c.683C>T(p.Pro228Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000347 in 1,604,770 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00034 ( 0 hom. )

Consequence

PPA2
NM_176869.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 9.48

Publications

14 publications found

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 Gene-Disease associations (from GenCC):

sudden cardiac failure, infantile
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Ambry Genetics, Labcorp Genetics (formerly Invitae)
dilated cardiomyopathy
Inheritance: AR Classification: STRONG Submitted by: ClinGen

PPA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PP5

Variant 4-105399137-G-A is Pathogenic according to our data. Variant chr4-105399137-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 372226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PPA2	NM_176869.3	MANE Select	c.683C>T	p.Pro228Leu	missense	Exon 8 of 12	NP_789845.1	Q9H2U2-1
PPA2	NM_006903.4		c.596C>T	p.Pro199Leu	missense	Exon 7 of 11	NP_008834.3	Q9H2U2-3
PPA2	NM_176866.2		c.377C>T	p.Pro126Leu	missense	Exon 4 of 8	NP_789842.2	Q9H2U2-6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PPA2	ENST00000341695.10	TSL:1 MANE Select	c.683C>T	p.Pro228Leu	missense	Exon 8 of 12	ENSP00000343885.5	Q9H2U2-1
PPA2	ENST00000348706.9	TSL:1	c.596C>T	p.Pro199Leu	missense	Exon 7 of 11	ENSP00000313061.8	Q9H2U2-3
PPA2	ENST00000432483.6	TSL:1	c.377C>T	p.Pro126Leu	missense	Exon 4 of 8	ENSP00000389957.2	Q9H2U2-6

Frequencies

GnomAD3 genomes

AF:

0.000434

AC:

AN:

152018

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000945

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000471

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000202

AC:

AN:

242474

AF XY:

0.000206

show subpopulations

Gnomad AFR exome

AF:

0.000127

Gnomad AMR exome

AF:

0.000217

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000484

Gnomad NFE exome

AF:

0.000332

Gnomad OTH exome

AF:

0.000338

GnomAD4 exome

AF:

0.000338

AC:

491

AN:

1452634

Hom.:

Cov.:

AF XY:

0.000328

AC XY:

237

AN XY:

722198

show subpopulations

African (AFR)

AF:

0.000122

AC:

AN:

32908

American (AMR)

AF:

0.000416

AC:

AN:

43272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25996

East Asian (EAS)

AF:

0.00

AC:

AN:

39534

South Asian (SAS)

AF:

0.0000120

AC:

AN:

83632

European-Finnish (FIN)

AF:

0.0000383

AC:

AN:

52246

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.000407

AC:

452

AN:

1109232

Other (OTH)

AF:

0.000233

AC:

AN:

60076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.436

Heterozygous variant carriers

101

126

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000434

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41524

American (AMR)

AF:

0.00164

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.0000945

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000471

AC:

AN:

67986

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000346

Hom.:

Bravo

AF:

0.000623

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000247

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Sudden cardiac failure, infantile (3)

Inborn genetic diseases (1)

Sudden cardiac failure, alcohol-induced (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Uncertain

0.088

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.098

MetaRNN

Uncertain

0.42

MetaSVM

Uncertain

0.66

MutationAssessor

Pathogenic

4.3

PhyloP100

9.5

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-9.6

REVEL

Uncertain

0.55

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.84

MVP

0.89

MPC

0.49

ClinPred

1.0

GERP RS

5.9

Varity_R

0.97

gMVP

0.82

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over