rs149054698

Positions:

• chr11-66848963-C-G
• chr11-66848963-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001040716.2(PC):​c.3473G>C​(p.Arg1158Pro) variant causes a missense change involving the alteration of a non-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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.766

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 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
PC	NM_001040716.2	c.3473G>C	p.Arg1158Pro	missense_variant	23/23	ENST00000393960.7	NP_001035806.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PC	ENST00000393960.7	c.3473G>C	p.Arg1158Pro	missense_variant	23/23	5	NM_001040716.2	ENSP00000377532	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T;D;D;D
Eigen	Benign	-0.063
Eigen_PC	Benign	-0.020
FATHMM_MKL	Benign	0.45	N
LIST_S2	Uncertain	0.96	.;.;.;D
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.56	D;D;D;D
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.9	.;L;L;L
MutationTaster	Benign	0.94	D;D;D;D
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.6	D;D;D;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.015	D;D;D;D
Sift4G	Uncertain	0.014	D;D;D;D
Polyphen		0.41	.;B;B;B
Vest4		0.48
MutPred		0.66		.;Gain of disorder (P = 0.0593);Gain of disorder (P = 0.0593);Gain of disorder (P = 0.0593);
MVP		0.63
MPC		0.73
ClinPred		0.79	D
GERP RS		1.8
Varity_R		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs149054698; hg19: chr11-66616434;