Genetic Variant NM_176869.3:c.881A>C (chr4-105386625-T-G) – 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.881A>C(p.Gln294Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q294R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

PPA2
NM_176869.3 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 2.76

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:

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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 4-105386625-T-G is Pathogenic according to our data. Variant chr4-105386625-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 372221.Status of the report is no_assertion_criteria_provided, 0 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
PPA2	NM_176869.3	MANE Select	c.881A>C	p.Gln294Pro	missense	Exon 10 of 12	NP_789845.1
PPA2	NM_006903.4		c.794A>C	p.Gln265Pro	missense	Exon 9 of 11	NP_008834.3
PPA2	NM_176866.2		c.575A>C	p.Gln192Pro	missense	Exon 6 of 8	NP_789842.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PPA2	ENST00000341695.10	TSL:1 MANE Select	c.881A>C	p.Gln294Pro	missense	Exon 10 of 12	ENSP00000343885.5
PPA2	ENST00000348706.9	TSL:1	c.794A>C	p.Gln265Pro	missense	Exon 9 of 11	ENSP00000313061.8
PPA2	ENST00000432483.6	TSL:1	c.575A>C	p.Gln192Pro	missense	Exon 6 of 8	ENSP00000389957.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.00083

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.043

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.71

M_CAP

Benign

0.014

MetaRNN

Uncertain

0.71

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

PhyloP100

2.8

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.5

REVEL

Benign

0.16

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.044

Polyphen

0.43

Vest4

0.90

MutPred

0.44

Loss of catalytic residue at Q294 (P = 0.0276)

MVP

0.59

MPC

0.39

ClinPred

0.90

GERP RS

5.0

Varity_R

0.41

gMVP

0.79

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over