chr4-105396272-C-G

Position:

• chr4-105396272-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_176869.3(PPA2):​c.846G>C​(p.Lys282Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.45 in 1,585,366 control chromosomes in the GnomAD database, including 167,646 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.37 (12583 hom., cov: 32)
  • Exomes 𝑓: 0.46 (155063 hom.)
• Consequence: PPA2 NM_176869.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• 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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0045214E-5).
• BP6: Variant 4-105396272-C-G is Benign according to our data. Variant chr4-105396272-C-G is described in ClinVar as [Benign]. Clinvar id is 1270616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-105396272-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.662 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPA2	NM_176869.3	c.846G>C	p.Lys282Asn	missense_variant	9/12	ENST00000341695.10	NP_789845.1
PPA2	NM_006903.4	c.759G>C	p.Lys253Asn	missense_variant	8/11		NP_008834.3
PPA2	NM_176866.2	c.540G>C	p.Lys180Asn	missense_variant	5/8		NP_789842.2
PPA2	NM_176867.3	c.348G>C	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>C	p.Lys282Asn	missense_variant	9/12	1	NM_176869.3	ENSP00000343885.5

Frequencies

GnomAD3 genomes AF: 0.374 AC: 56792 AN: 151874 Hom.: 12573 Cov.: 32

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.441

Gnomad AMR AF: 0.484

Gnomad ASJ AF: 0.422

Gnomad EAS AF: 0.680

Gnomad SAS AF: 0.521

Gnomad FIN AF: 0.412

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.457

Gnomad OTH AF: 0.381

GnomAD3 exomes AF: 0.448 AC: 105583 AN: 235754 Hom.: 25264 AF XY: 0.452 AC XY: 57728 AN XY: 127788

Gnomad AFR exome AF: 0.112

Gnomad AMR exome AF: 0.515

Gnomad ASJ exome AF: 0.425

Gnomad EAS exome AF: 0.652

Gnomad SAS exome AF: 0.490

Gnomad FIN exome AF: 0.421

Gnomad NFE exome AF: 0.445

Gnomad OTH exome AF: 0.434

GnomAD4 exome AF: 0.458 AC: 656349 AN: 1433374 Hom.: 155063 Cov.: 30 AF XY: 0.459 AC XY: 327484 AN XY: 713006

Gnomad4 AFR exome AF: 0.109

Gnomad4 AMR exome AF: 0.513

Gnomad4 ASJ exome AF: 0.428

Gnomad4 EAS exome AF: 0.708

Gnomad4 SAS exome AF: 0.494

Gnomad4 FIN exome AF: 0.417

Gnomad4 NFE exome AF: 0.459

Gnomad4 OTH exome AF: 0.440

GnomAD4 genome AF: 0.374 AC: 56811 AN: 151992 Hom.: 12583 Cov.: 32 AF XY: 0.376 AC XY: 27944 AN XY: 74262

Gnomad4 AFR AF: 0.126

Gnomad4 AMR AF: 0.484

Gnomad4 ASJ AF: 0.422

Gnomad4 EAS AF: 0.681

Gnomad4 SAS AF: 0.520

Gnomad4 FIN AF: 0.412

Gnomad4 NFE AF: 0.457

Gnomad4 OTH AF: 0.385

Alfa AF: 0.440 Hom.: 11420

Bravo AF: 0.367

TwinsUK AF: 0.468 AC: 1736

ALSPAC AF: 0.462 AC: 1781

ESP6500AA AF: 0.133 AC: 585

ESP6500EA AF: 0.457 AC: 3925

ExAC AF: 0.454 AC: 55093

Asia WGS AF: 0.582 AC: 2019 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 06, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Sudden cardiac failure, infantile Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.66	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	0.10	N
LIST_S2	Benign	0.66	T;T;T;T
MetaRNN	Benign	0.000010	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.3	M;.;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.6	D;D;D;D
REVEL	Benign	0.099
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);.;.;.;
MPC		0.19
ClinPred		0.037	T
GERP RS		0.10
Varity_R		0.20
gMVP		0.66

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

LitVar

Other links and lift over

dbSNP: rs13787; hg19: chr4-106317429; COSMIC: COSV58995765; COSMIC: COSV58995765;