Genetic Variant PC:c.-1+29447G>A (chr11-66922983-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.620

Publications

15 publications found

Variant links:

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]

PC Gene-Disease associations (from GenCC):

pyruvate carboxylase deficiency disease
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)
pyruvate carboxylase deficiency, benign type
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
pyruvate carboxylase deficiency, infantile form
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
pyruvate carboxylase deficiency, severe neonatal type
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PC links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040716.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PC	NM_001040716.2	MANE Select	c.-1+29447G>A	intron	N/A	NP_001035806.1	P11498-1
PC	NM_000920.4		c.-1+29447G>A	intron	N/A	NP_000911.2	P11498-1
PC	NM_001439352.1		c.-1+29447G>A	intron	N/A	NP_001426281.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PC	ENST00000393960.7	TSL:5 MANE Select	c.-1+29447G>A	intron	N/A	ENSP00000377532.1	P11498-1
PC	ENST00000393958.7	TSL:1	c.-1+29447G>A	intron	N/A	ENSP00000377530.2	P11498-1
PC	ENST00000525476.2	TSL:1	n.289+29447G>A	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.303

AC:

46105

AN:

152008

Hom.:

7725

Cov.:

show subpopulations

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.:

AF XY:

0.305

AC XY:

22670

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.186

AC:

7705

AN:

41512

American (AMR)

AF:

0.290

AC:

4433

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.387

AC:

1342

AN:

3472

East Asian (EAS)

AF:

0.422

AC:

2187

AN:

5180

South Asian (SAS)

AF:

0.586

AC:

2827

AN:

4826

European-Finnish (FIN)

AF:

0.232

AC:

2456

AN:

10576

Middle Eastern (MID)

AF:

0.435

AC:

128

AN:

294

European-Non Finnish (NFE)

AF:

0.351

AC:

23832

AN:

67980

Other (OTH)

AF:

0.364

AC:

767

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1592

3184

4775

6367

7959

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

492

984

1476

1968

2460

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.330

Hom.:

27415

Bravo

AF:

0.294

Asia WGS

AF:

0.453

AC:

1577

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

2.6

(source)

DANN

Benign

0.47

PhyloP100

0.62

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over