4-105449353-C-G

Variant names:

• chr4-105449353-C-G
• NM_176869.3:c.318G>C
• PPA2 p.Met106Ile

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS1 PM1 PM2 PP3

The NM_176869.3(PPA2):​c.318G>C​(p.Met106Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PPA2 NM_176869.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.60
• 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, Labcorp Genetics (formerly Invitae), Ambry Genetics
• dilated cardiomyopathy

  Inheritance: AR Classification: STRONG Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PS1: Transcript NM_176869.3 (PPA2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_176869.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.772

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.318G>C	p.Met106Ile	missense	Exon 4 of 12	NP_789845.1	Q9H2U2-1
	PPA2	NM_006903.4		c.318G>C	p.Met106Ile	missense	Exon 4 of 11	NP_008834.3	Q9H2U2-3
	PPA2	NM_176866.2		c.222+7328G>C		intron	N/A	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.318G>C	p.Met106Ile	missense	Exon 4 of 12	ENSP00000343885.5	Q9H2U2-1
	PPA2	ENST00000348706.9	TSL:1	c.318G>C	p.Met106Ile	missense	Exon 4 of 11	ENSP00000313061.8	Q9H2U2-3
	PPA2	ENST00000432483.6	TSL:1	c.222+7328G>C		intron	N/A	ENSP00000389957.2	Q9H2U2-6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.032	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.35	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		7.6
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.62
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.045	D
PromoterAI		-0.020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.67
gMVP		0.88
Mutation Taster		=5/95	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr4-106370510;