dbSNP rs1057517679: PPA2:p.Met94Val (chr4-105449391-T-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP5

The NM_176869.3(PPA2):c.280A>G(p.Met94Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000014 in 1,425,268 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PPA2
NM_176869.3 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 4.84

Publications

3 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine

PPA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 4-105449391-T-C is Pathogenic according to our data. Variant chr4-105449391-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 372223.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPA2	NM_176869.3 link	c.280A>G	p.Met94Val	missense_variant	Exon 4 of 12	ENST00000341695.10	NP_789845.1	Q9H2U2-1
PPA2	NM_006903.4 link	c.280A>G	p.Met94Val	missense_variant	Exon 4 of 11		NP_008834.3	Q9H2U2-3
PPA2	NM_176866.2 link	c.222+7290A>G		intron_variant	Intron 2 of 7		NP_789842.2	Q9H2U2-6
PPA2	NM_176867.3 link	c.157+24503A>G		intron_variant	Intron 1 of 5		NP_789843.2	Q9H2U2-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPA2	ENST00000341695.10 link	c.280A>G	p.Met94Val	missense_variant	Exon 4 of 12	1	NM_176869.3	ENSP00000343885.5		Q9H2U2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000140

AC:

AN:

1425268

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

710656

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32118

American (AMR)

AF:

0.00

AC:

AN:

40782

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25512

East Asian (EAS)

AF:

0.00

AC:

AN:

39228

South Asian (SAS)

AF:

0.00

AC:

AN:

83208

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53042

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5636

European-Non Finnish (NFE)

AF:

0.00000184

AC:

AN:

1086608

Other (OTH)

AF:

0.00

AC:

AN:

59134

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Sudden cardiac failure, infantile

Pathogenic:1

Nov 23, 2016

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.079

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.24

T;.;T;.

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.98

D;D;D;D

M_CAP

Benign

0.018

MetaRNN

Uncertain

0.51

D;D;D;D

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.1

M;M;.;.

PhyloP100

4.8

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.3

D;D;D;D

REVEL

Benign

0.16

Sift

Benign

0.046

D;T;D;T

Sift4G

Benign

0.064

T;D;.;T

Polyphen

0.95

P;P;.;.

Vest4

0.85

MutPred

0.64

Loss of stability (P = 0.1129);Loss of stability (P = 0.1129);.;.;

MVP

0.33

MPC

0.49

ClinPred

0.97

GERP RS

5.7

PromoterAI

0.0048

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Varity_R

0.58

gMVP

0.87

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over