chr4-105370605-C-T

Variant names:

• chr4-105370605-C-T
• rs36112402
• NM_176869.3:c.976+232G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_176869.3(PPA2):​c.976+232G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.235 in 970,802 control chromosomes in the GnomAD database, including 27,665 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.25 (4868 hom., cov: 32)
  • Exomes 𝑓: 0.23 (22797 hom.)
• Consequence: PPA2 NM_176869.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.308
• Publications: 2 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 4-105370605-C-T is Benign according to our data. Variant chr4-105370605-C-T is described in ClinVar as Benign. ClinVar VariationId is 1296656.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.421 is higher than 0.05.

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.976+232G>A		intron	N/A	NP_789845.1	Q9H2U2-1
	PPA2	NM_006903.4		c.889+232G>A		intron	N/A	NP_008834.3	Q9H2U2-3
	PPA2	NM_176866.2		c.670+232G>A		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.976+232G>A		intron	N/A	ENSP00000343885.5	Q9H2U2-1
	PPA2	ENST00000348706.9	TSL:1	c.889+232G>A		intron	N/A	ENSP00000313061.8	Q9H2U2-3
	PPA2	ENST00000432483.6	TSL:1	c.670+232G>A		intron	N/A	ENSP00000389957.2	Q9H2U2-6

Frequencies

GnomAD3 genomes AF: 0.251 AC: 37862 AN: 150980 Hom.: 4855 Cov.: 32

Gnomad AFR AF: 0.239

Gnomad AMI AF: 0.181

Gnomad AMR AF: 0.296

Gnomad ASJ AF: 0.244

Gnomad EAS AF: 0.436

Gnomad SAS AF: 0.222

Gnomad FIN AF: 0.209

Gnomad MID AF: 0.268

Gnomad NFE AF: 0.243

Gnomad OTH AF: 0.259

GnomAD4 exome AF: 0.232 AC: 190305 AN: 819704 Hom.: 22797 Cov.: 23 AF XY: 0.231 AC XY: 87457 AN XY: 378940

African (AFR) AF: 0.241 AC: 3737 AN: 15510

American (AMR) AF: 0.314 AC: 300 AN: 956

Ashkenazi Jewish (ASJ) AF: 0.217 AC: 1100 AN: 5068

East Asian (EAS) AF: 0.428 AC: 1497 AN: 3494

South Asian (SAS) AF: 0.213 AC: 3434 AN: 16158

European-Finnish (FIN) AF: 0.184 AC: 50 AN: 272

Middle Eastern (MID) AF: 0.223 AC: 358 AN: 1602

European-Non Finnish (NFE) AF: 0.231 AC: 173172 AN: 749830

Other (OTH) AF: 0.248 AC: 6657 AN: 26814

GnomAD4 genome AF: 0.251 AC: 37930 AN: 151098 Hom.: 4868 Cov.: 32 AF XY: 0.251 AC XY: 18502 AN XY: 73734

African (AFR) AF: 0.239 AC: 9874 AN: 41244

American (AMR) AF: 0.296 AC: 4493 AN: 15204

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 846 AN: 3464

East Asian (EAS) AF: 0.436 AC: 2244 AN: 5142

South Asian (SAS) AF: 0.222 AC: 1061 AN: 4790

European-Finnish (FIN) AF: 0.209 AC: 2130 AN: 10212

Middle Eastern (MID) AF: 0.260 AC: 76 AN: 292

European-Non Finnish (NFE) AF: 0.243 AC: 16490 AN: 67748

Other (OTH) AF: 0.264 AC: 551 AN: 2090

Alfa AF: 0.137 Hom.: 253

Bravo AF: 0.256

Asia WGS AF: 0.355 AC: 1220 AN: 3432

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.2
DANN	Benign	0.48
PhyloP100		-0.31
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs36112402; hg19: chr4-106291762;