Genetic Variant PPA2:c.976+315dupA (chr4-105370521-G-GT) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_176869.3(PPA2):c.976+315dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000629 in 796,244 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000073 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00076 ( 0 hom. )

Consequence

PPA2
NM_176869.3 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0620

Publications

0 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: Uncertain_significance. The variant received 0 ACMG points.

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	Effect	Exon Rank	Protein	UniProt
PPA2	NM_176869.3	MANE Select	c.976+315dupA	intron	N/A	NP_789845.1	Q9H2U2-1
PPA2	NM_006903.4		c.889+315dupA	intron	N/A	NP_008834.3	Q9H2U2-3
PPA2	NM_176866.2		c.670+315dupA	intron	N/A	NP_789842.2	Q9H2U2-6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PPA2	ENST00000341695.10	TSL:1 MANE Select	c.976+315_976+316insA	intron	N/A	ENSP00000343885.5	Q9H2U2-1
PPA2	ENST00000348706.9	TSL:1	c.889+315_889+316insA	intron	N/A	ENSP00000313061.8	Q9H2U2-3
PPA2	ENST00000432483.6	TSL:1	c.670+315_670+316insA	intron	N/A	ENSP00000389957.2	Q9H2U2-6

Frequencies

GnomAD3 genomes

AF:

0.0000733

AC:

AN:

149982

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000736

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000265

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000445

Gnomad OTH

AF:

0.000481

GnomAD4 exome

AF:

0.000758

AC:

490

AN:

646262

Hom.:

Cov.:

AF XY:

0.000711

AC XY:

214

AN XY:

301110

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000165

AC:

AN:

12098

American (AMR)

AF:

0.00

AC:

AN:

706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

4056

East Asian (EAS)

AF:

0.000378

AC:

AN:

2644

South Asian (SAS)

AF:

0.00120

AC:

AN:

12490

European-Finnish (FIN)

AF:

0.00

AC:

AN:

218

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1250

European-Non Finnish (NFE)

AF:

0.000772

AC:

457

AN:

591874

Other (OTH)

AF:

0.000717

AC:

AN:

20926

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.254

Heterozygous variant carriers

165

247

330

412

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

<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:

0.0000733

AC:

AN:

149982

Hom.:

Cov.:

AF XY:

0.0000683

AC XY:

AN XY:

73178

show subpopulations

African (AFR)

AF:

0.0000736

AC:

AN:

40778

American (AMR)

AF:

0.000265

AC:

AN:

15084

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3450

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4772

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9974

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.0000445

AC:

AN:

67458

Other (OTH)

AF:

0.000481

AC:

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

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:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.062

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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4-105370521-GT-GTT

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