NM_176869.3:c.976+246delT

Variant names:

• chr4-105370590-GA-G
• rs34420247
• NM_176869.3:c.976+246delT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_176869.3(PPA2):​c.976+246delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 961,456 control chromosomes in the GnomAD database, including 6,239 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.13 (1576 hom., cov: 30)
  • Exomes 𝑓: 0.10 (4663 hom.)
• Consequence: PPA2 NM_176869.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0850
• 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 -10 ACMG points.

• BP6: Variant 4-105370590-GA-G is Benign according to our data. Variant chr4-105370590-GA-G is described in ClinVar as Benign. ClinVar VariationId is 1277752.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.418 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+246delT		intron	N/A	NP_789845.1	Q9H2U2-1
	PPA2	NM_006903.4		c.889+246delT		intron	N/A	NP_008834.3	Q9H2U2-3
	PPA2	NM_176866.2		c.670+246delT		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+246delT		intron	N/A	ENSP00000343885.5	Q9H2U2-1
	PPA2	ENST00000348706.9	TSL:1	c.889+246delT		intron	N/A	ENSP00000313061.8	Q9H2U2-3
	PPA2	ENST00000432483.6	TSL:1	c.670+246delT		intron	N/A	ENSP00000389957.2	Q9H2U2-6

Frequencies

GnomAD3 genomes AF: 0.131 AC: 19211 AN: 146928 Hom.: 1564 Cov.: 30

Gnomad AFR AF: 0.0923

Gnomad AMI AF: 0.0235

Gnomad AMR AF: 0.194

Gnomad ASJ AF: 0.155

Gnomad EAS AF: 0.432

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.151

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.130

GnomAD4 exome AF: 0.103 AC: 84035 AN: 814432 Hom.: 4663 Cov.: 0 AF XY: 0.103 AC XY: 38713 AN XY: 376570

African (AFR) AF: 0.0867 AC: 1334 AN: 15394

American (AMR) AF: 0.212 AC: 203 AN: 956

Ashkenazi Jewish (ASJ) AF: 0.135 AC: 684 AN: 5058

East Asian (EAS) AF: 0.416 AC: 1443 AN: 3470

South Asian (SAS) AF: 0.139 AC: 2233 AN: 16046

European-Finnish (FIN) AF: 0.102 AC: 27 AN: 266

Middle Eastern (MID) AF: 0.145 AC: 231 AN: 1592

European-Non Finnish (NFE) AF: 0.100 AC: 74572 AN: 745018

Other (OTH) AF: 0.124 AC: 3308 AN: 26632

GnomAD4 genome AF: 0.131 AC: 19267 AN: 147024 Hom.: 1576 Cov.: 30 AF XY: 0.135 AC XY: 9668 AN XY: 71372

African (AFR) AF: 0.0931 AC: 3729 AN: 40046

American (AMR) AF: 0.194 AC: 2870 AN: 14818

Ashkenazi Jewish (ASJ) AF: 0.155 AC: 535 AN: 3448

East Asian (EAS) AF: 0.433 AC: 2208 AN: 5102

South Asian (SAS) AF: 0.156 AC: 732 AN: 4686

European-Finnish (FIN) AF: 0.128 AC: 1146 AN: 8988

Middle Eastern (MID) AF: 0.150 AC: 42 AN: 280

European-Non Finnish (NFE) AF: 0.115 AC: 7704 AN: 66722

Other (OTH) AF: 0.137 AC: 280 AN: 2040

Alfa AF: 0.0479 Hom.: 47

Bravo AF: 0.132

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
PhyloP100		0.085
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: rs34420247; hg19: chr4-106291747;