rs1555015018

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PP2PP3_StrongPP5_Moderate

The NM_001040716.2(PC):​c.2606G>C​(p.Gly869Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 33)

Consequence

PC
NM_001040716.2 missense

Scores

14
4
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 3.67
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 Likely_pathogenic. Variant got 9 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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.99
PP5
Variant 11-66850332-C-G is Pathogenic according to our data. Variant chr11-66850332-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1315510.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PCNM_001040716.2 linkuse as main transcriptc.2606G>C p.Gly869Ala 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.2606G>C p.Gly869Ala 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

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Pyruvate carboxylase deficiency Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingLaboratory of Inherited Metabolic Diseases, Research centre for medical geneticsOct 28, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.26
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.74
D;D;D
Eigen
Pathogenic
0.97
Eigen_PC
Pathogenic
0.83
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Pathogenic
1.0
.;.;D
M_CAP
Pathogenic
0.79
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.9
H;H;H
PrimateAI
Uncertain
0.78
T
PROVEAN
Pathogenic
-5.7
D;D;D
REVEL
Pathogenic
0.91
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
D;D;D
Vest4
0.96
MutPred
0.91
Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);
MVP
0.88
MPC
1.3
ClinPred
1.0
D
GERP RS
4.7
Varity_R
0.95

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.090
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-66617803; API