NM_176869.3:c.976+170C>T

Variant names:

• chr4-105370667-G-A
• rs11301777
• NM_176869.3:c.976+170C>T

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+170C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.242 in 931,228 control chromosomes in the GnomAD database, including 28,467 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.29 (6741 hom., cov: 32)
  • Exomes 𝑓: 0.23 (21726 hom.)
• Consequence: PPA2 NM_176869.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0710
• Publications: 0 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=-0.92).
• BP6: Variant 4-105370667-G-A is Benign according to our data. Variant chr4-105370667-G-A is described in ClinVar as Benign. ClinVar VariationId is 1246086.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.422 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+170C>T		intron	N/A	NP_789845.1	Q9H2U2-1
	PPA2	NM_006903.4		c.889+170C>T		intron	N/A	NP_008834.3	Q9H2U2-3
	PPA2	NM_176866.2		c.670+170C>T		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+170C>T		intron	N/A	ENSP00000343885.5	Q9H2U2-1
	PPA2	ENST00000348706.9	TSL:1	c.889+170C>T		intron	N/A	ENSP00000313061.8	Q9H2U2-3
	PPA2	ENST00000432483.6	TSL:1	c.670+170C>T		intron	N/A	ENSP00000389957.2	Q9H2U2-6

Frequencies

GnomAD3 genomes AF: 0.290 AC: 43966 AN: 151542 Hom.: 6724 Cov.: 32

Gnomad AFR AF: 0.376

Gnomad AMI AF: 0.181

Gnomad AMR AF: 0.312

Gnomad ASJ AF: 0.244

Gnomad EAS AF: 0.437

Gnomad SAS AF: 0.222

Gnomad FIN AF: 0.207

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.244

Gnomad OTH AF: 0.286

GnomAD4 exome AF: 0.233 AC: 181490 AN: 779564 Hom.: 21726 Cov.: 13 AF XY: 0.231 AC XY: 83531 AN XY: 361168

African (AFR) AF: 0.387 AC: 5652 AN: 14600

American (AMR) AF: 0.314 AC: 281 AN: 894

Ashkenazi Jewish (ASJ) AF: 0.217 AC: 1042 AN: 4810

East Asian (EAS) AF: 0.426 AC: 1398 AN: 3282

South Asian (SAS) AF: 0.209 AC: 3192 AN: 15270

European-Finnish (FIN) AF: 0.178 AC: 46 AN: 258

Middle Eastern (MID) AF: 0.229 AC: 352 AN: 1540

European-Non Finnish (NFE) AF: 0.229 AC: 163077 AN: 713444

Other (OTH) AF: 0.253 AC: 6450 AN: 25466

GnomAD4 genome AF: 0.290 AC: 44039 AN: 151664 Hom.: 6741 Cov.: 32 AF XY: 0.289 AC XY: 21377 AN XY: 74078

African (AFR) AF: 0.376 AC: 15574 AN: 41394

American (AMR) AF: 0.312 AC: 4753 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 847 AN: 3470

East Asian (EAS) AF: 0.437 AC: 2256 AN: 5162

South Asian (SAS) AF: 0.222 AC: 1068 AN: 4820

European-Finnish (FIN) AF: 0.207 AC: 2155 AN: 10390

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.244 AC: 16533 AN: 67866

Other (OTH) AF: 0.290 AC: 611 AN: 2108

Alfa AF: 0.277 Hom.: 806

Bravo AF: 0.302

Asia WGS AF: 0.360 AC: 1235 AN: 3426

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	-0.92
CADD	Benign	7.0
DANN	Benign	0.62
PhyloP100		0.071
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: rs11301777; hg19: chr4-106291824;