4-105369748-C-T

Variant names:

• chr4-105369748-C-T
• rs1425488238
• NM_176869.3:c.982G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_176869.3(PPA2):​c.982G>A​(p.Val328Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V328L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PPA2 NM_176869.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.216
• Publications: 1 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.049607515).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPA2	NM_176869.3	MANE Select	c.982G>A	p.Val328Met	missense	Exon 12 of 12	NP_789845.1	Q9H2U2-1
	PPA2	NM_006903.4		c.895G>A	p.Val299Met	missense	Exon 11 of 11	NP_008834.3	Q9H2U2-3
	PPA2	NM_176866.2		c.676G>A	p.Val226Met	missense	Exon 8 of 8	NP_789842.2	Q9H2U2-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPA2	ENST00000341695.10	TSL:1 MANE Select	c.982G>A	p.Val328Met	missense	Exon 12 of 12	ENSP00000343885.5	Q9H2U2-1
	PPA2	ENST00000348706.9	TSL:1	c.895G>A	p.Val299Met	missense	Exon 11 of 11	ENSP00000313061.8	Q9H2U2-3
	PPA2	ENST00000432483.6	TSL:1	c.676G>A	p.Val226Met	missense	Exon 8 of 8	ENSP00000389957.2	Q9H2U2-6

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152064 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1437304 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 716282

African (AFR) AF: 0.00 AC: 0 AN: 32850

American (AMR) AF: 0.00 AC: 0 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25996

East Asian (EAS) AF: 0.00 AC: 0 AN: 39562

South Asian (SAS) AF: 0.00 AC: 0 AN: 85734

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1089736

Other (OTH) AF: 0.00 AC: 0 AN: 59654

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152064 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74252

African (AFR) AF: 0.00 AC: 0 AN: 41408

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.035	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		-0.22
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.040
Sift	Benign	0.081	T
Sift4G	Benign	0.11	T
Polyphen		0.070	B
Vest4		0.044
MutPred		0.24		Loss of sheet (P = 0.0817)
MVP		0.16
MPC		0.097
ClinPred		0.072	T
GERP RS		0.0081
Varity_R		0.027
gMVP		0.39
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs1425488238; hg19: chr4-106290905;