rs13787

Positions:

• chr4-105396272-C-A
• chr4-105396272-C-G
• chr4-105396272-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_176869.3(PPA2):​c.846G>T​(p.Lys282Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,439,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PPA2 NM_176869.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.173

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10154873).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPA2	NM_176869.3	c.846G>T	p.Lys282Asn	missense_variant	9/12	ENST00000341695.10	NP_789845.1
PPA2	NM_006903.4	c.759G>T	p.Lys253Asn	missense_variant	8/11		NP_008834.3
PPA2	NM_176866.2	c.540G>T	p.Lys180Asn	missense_variant	5/8		NP_789842.2
PPA2	NM_176867.3	c.348G>T	p.Lys116Asn	missense_variant	3/6		NP_789843.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPA2	ENST00000341695.10	c.846G>T	p.Lys282Asn	missense_variant	9/12	1	NM_176869.3	ENSP00000343885	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1439990 Hom.: 0 Cov.: 30 AF XY: 0.00000140 AC XY: 1 AN XY: 716394

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000122

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T;.;.;.
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.66	T;T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.10	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.3	M;.;.;.
MutationTaster	Benign	0.96	P;P;P;P;P;P
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.6	D;D;D;D
REVEL	Benign	0.10
Sift	Benign	0.069	T;T;T;T
Sift4G	Benign	0.16	T;T;D;T
Polyphen		0.038	B;B;P;.
Vest4		0.066
MutPred		0.18		Loss of methylation at K282 (P = 0.0027);.;.;.;
MVP		0.43
MPC		0.19
ClinPred		0.97	D
GERP RS		0.10
Varity_R		0.20
gMVP		0.66

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

LitVar

Other links and lift over

dbSNP: rs13787; hg19: chr4-106317429;