rs772083375

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_176869.3(PPA2):c.182C>T(p.Ser61Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000151 in 1,454,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

PPA2
NM_176869.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 7.08

Publications

5 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:

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ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.94

PP5

Variant 4-105456721-G-A is Pathogenic according to our data. Variant chr4-105456721-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 372220.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
PPA2	NM_176869.3 link	c.182C>T	p.Ser61Phe	missense_variant	Exon 2 of 12	ENST00000341695.10	NP_789845.1
PPA2	NM_006903.4 link	c.182C>T	p.Ser61Phe	missense_variant	Exon 2 of 11		NP_008834.3
PPA2	NM_176866.2 link	c.182C>T	p.Ser61Phe	missense_variant	Exon 2 of 8		NP_789842.2
PPA2	NM_176867.3 link	c.157+17173C>T		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 link	c.182C>T	p.Ser61Phe	missense_variant	Exon 2 of 12	1	NM_176869.3	ENSP00000343885.5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000809

AC:

AN:

247094

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000890

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1454778

Hom.:

Cov.:

AF XY:

0.0000111

AC XY:

AN XY:

723916

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33170

American (AMR)

AF:

0.00

AC:

AN:

43490

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26020

East Asian (EAS)

AF:

0.00

AC:

AN:

39392

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85332

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53314

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.0000180

AC:

AN:

1108184

Other (OTH)

AF:

0.0000166

AC:

AN:

60138

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

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.:

Alfa

AF:

0.000111

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Sudden cardiac failure, infantile

Pathogenic:2

Nov 23, 2016

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Sep 14, 2017

Royal Brompton Clinical Genetics And Genomics Laboratory, NHS South East Genomic Laboratory Hub

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.182C>T variant is present in 2/242228 individuals in the gnomAD control population in heterozygous form, and has previously been reported in compound heterozygosity with another likely pathogenic PPA2 variant in four siblings with sudden infantile cardiac failure, showing autosomal recessive inheritance (Guimier et al (2016) Am J Hum Genet 99(3):666-673). In silico analysis predicts a pathogenic effect on protein function and the affected amino acid is highly conserved. Functional studies indicated that this variant adversely affects protein function (Guimier et al (2016)). The variant was detected in compound heterozygosity with another pathogenic variant in the proband, and in heterozygous form in an unaffected parent. In view of this evidence, we have interpreted this variant as likely to be pathogenic when inherited with another (likely) pathogenic variant. The variant is likely to be benign when carried in isolation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.57

D;.;.;T;T

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.93

D;D;D;D;D

M_CAP

Benign

0.028

MetaRNN

Pathogenic

0.94

D;D;D;D;D

MetaSVM

Uncertain

-0.21

MutationAssessor

Uncertain

2.7

M;M;M;.;.

PhyloP100

7.1

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-5.0

D;D;D;D;D

REVEL

Uncertain

0.52

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;T;.

Polyphen

0.96

P;P;.;.;.

Vest4

0.98

MutPred

0.85

Gain of catalytic residue at S61 (P = 0.0822);Gain of catalytic residue at S61 (P = 0.0822);Gain of catalytic residue at S61 (P = 0.0822);Gain of catalytic residue at S61 (P = 0.0822);Gain of catalytic residue at S61 (P = 0.0822);

MVP

0.79

MPC

0.13

ClinPred

0.99

GERP RS

4.7

Varity_R

0.87

gMVP

0.97

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over