rs113994147

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_001040716.2(PC):​c.2540C>T​(p.Ala847Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Consequence

PC
NM_001040716.2 missense

Scores

4
11
4

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.25
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PC. . Gene score misZ 3.0552 (greater than the threshold 3.09). Trascript score misZ 3.7621 (greater than threshold 3.09). GenCC has associacion of gene with pyruvate carboxylase deficiency, benign type, pyruvate carboxylase deficiency, severe neonatal type, pyruvate carboxylase deficiency, infantile form, pyruvate carboxylase deficiency disease.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PCNM_001040716.2 linkuse as main transcriptc.2540C>T p.Ala847Val missense_variant 19/23 ENST00000393960.7 NP_001035806.1 P11498-1A0A024R5C5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PCENST00000393960.7 linkuse as main transcriptc.2540C>T p.Ala847Val missense_variant 19/235 NM_001040716.2 ENSP00000377532.1 P11498-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.24
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Uncertain
0.020
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.33
T;T;T
Eigen
Uncertain
0.39
Eigen_PC
Uncertain
0.48
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Pathogenic
0.99
.;.;D
M_CAP
Uncertain
0.16
D
MetaRNN
Uncertain
0.42
T;T;T
MetaSVM
Pathogenic
0.82
D
MutationAssessor
Uncertain
2.7
M;M;M
MutationTaster
Benign
1.0
A;A;A
PrimateAI
Uncertain
0.69
T
PROVEAN
Benign
-1.1
N;N;N
REVEL
Uncertain
0.50
Sift
Uncertain
0.0090
D;D;D
Sift4G
Uncertain
0.023
D;D;D
Polyphen
0.62
P;P;P
Vest4
0.43
MutPred
0.52
Gain of loop (P = 0.024);Gain of loop (P = 0.024);Gain of loop (P = 0.024);
MVP
0.54
MPC
0.51
ClinPred
0.93
D
GERP RS
4.8
Varity_R
0.38

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs113994147; hg19: chr11-66617869; API