11-66922983-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001040716.2(PC):c.-1+29447G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.303 in 152,126 control chromosomes in the GnomAD database, including 7,726 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.30 (7726 hom., cov: 31)
• Consequence: PC NM_001040716.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.620

Genes affected

PC (HGNC:8636): (pyruvate carboxylase) This gene encodes pyruvate carboxylase, which requires biotin and ATP to catalyse the carboxylation of pyruvate to oxaloacetate. The active enzyme is a homotetramer arranged in a tetrahedron which is located exclusively in the mitochondrial matrix. Pyruvate carboxylase is involved in gluconeogenesis, lipogenesis, insulin secretion and synthesis of the neurotransmitter glutamate. Mutations in this gene have been associated with pyruvate carboxylase deficiency. Alternatively spliced transcript variants with different 5' UTRs, but encoding the same protein, have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.568 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PC	NM_001040716.2	c.-1+29447G>A		intron_variant		ENST00000393960.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PC	ENST00000393960.7	c.-1+29447G>A		intron_variant		5	NM_001040716.2	P1

Frequencies

GnomAD3 genomes AF: 0.303 AC: 46105 AN: 152008 Hom.: 7725 Cov.: 31

Gnomad AFR AF: 0.186

Gnomad AMI AF: 0.470

Gnomad AMR AF: 0.290

Gnomad ASJ AF: 0.387

Gnomad EAS AF: 0.422

Gnomad SAS AF: 0.587

Gnomad FIN AF: 0.232

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.351

Gnomad OTH AF: 0.360

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.303 AC: 46105 AN: 152126 Hom.: 7726 Cov.: 31 AF XY: 0.305 AC XY: 22670 AN XY: 74354

Gnomad4 AFR AF: 0.186

Gnomad4 AMR AF: 0.290

Gnomad4 ASJ AF: 0.387

Gnomad4 EAS AF: 0.422

Gnomad4 SAS AF: 0.586

Gnomad4 FIN AF: 0.232

Gnomad4 NFE AF: 0.351

Gnomad4 OTH AF: 0.364

Alfa AF: 0.339 Hom.: 12336

Bravo AF: 0.294

Asia WGS AF: 0.453 AC: 1577 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	2.6
Dann	Benign	0.47

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: rs7110302; hg19: chr11-66690454;