rs147697454

chr11-66871189-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM1 PP2 BP4_Moderate BS1_Supporting

The NM_001040716.2(PC):c.496G>A(p.Val166Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000816 in 1,613,058 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00084 (2 hom.)
• Consequence: PC NM_001040716.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 3.39

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 0 ACMG points.

• PM1: In a domain ATP-grasp (size 197) in uniprot entity PYC_HUMAN there are 13 pathogenic changes around while only 5 benign (72%) in NM_001040716.2
• PP2: Missense variant where missense usually causes diseases, PC
• BP4: Computational evidence support a benign effect (MetaRNN=0.20321992).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000584 (89/152322) while in subpopulation AMR AF= 0.00157 (24/15310). AF 95% confidence interval is 0.00108. There are 0 homozygotes in gnomad4. There are 47 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PC	NM_001040716.2	c.496G>A	p.Val166Ile	missense_variant	7/23	ENST00000393960.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PC	ENST00000393960.7	c.496G>A	p.Val166Ile	missense_variant	7/23	5	NM_001040716.2	P1

Frequencies

GnomAD3 genomes AF: 0.000585 AC: 89 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000471 AC: 118 AN: 250760 Hom.: 0 AF XY: 0.000472 AC XY: 64 AN XY: 135478

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000812

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000705

Gnomad OTH exome AF: 0.000655

GnomAD4 exome AF: 0.000840 AC: 1227 AN: 1460736 Hom.: 2 Cov.: 33 AF XY: 0.000782 AC XY: 568 AN XY: 726444

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000717

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00102

Gnomad4 OTH exome AF: 0.000895

GnomAD4 genome AF: 0.000584 AC: 89 AN: 152322 Hom.: 0 Cov.: 32 AF XY: 0.000631 AC XY: 47 AN XY: 74472

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000706

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000711 Hom.: 0

Bravo AF: 0.000582

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000420 AC: 51

EpiCase AF: 0.000709

EpiControl AF: 0.000534

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Pyruvate carboxylase deficiency Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 08, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 21, 2023

Variant summary: PC c.496G>A (p.Val166Ile) results in a conservative amino acid change located in the Carbamoyl-phosphate synthetase large subunit-like, ATP-binding domain (IPR005479) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00047 in 250760 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in PC causing Pyruvate Carboxylase Deficiency (0.00047 vs 0.0022), allowing no conclusion about variant significance. c.496G>A has been reported in the literature in individuals affected with Pyruvate Carboxylase Deficiency without strong evidence of causality (Wang_2008). This report does not provide unequivocal conclusions about association of the variant with Pyruvate Carboxylase Deficiency. Co-occurrence with another pathogenic variant was reported in the patient (PC c.1892G>A, p.Arg631Gln), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 18676167). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=4) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 26, 2022

The c.496G>A (p.V166I) alteration is located in exon 6 (coding exon 4) of the PC gene. This alteration results from a G to A substitution at nucleotide position 496, causing the valine (V) at amino acid position 166 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 12, 2018

p.Val166Ile (GTT>ATT): c.496 G>A in exon 6 of the PC gene (NM_000920.3) A variant of unknown significance has been identified in the PC gene. The V166I variant has been published as a mutation in a patient with pyruvate carboxylase deficiency who was homozygous for V166I and homozygous for another missense change that results in a more severe amino acid substitution (Wang et al., 2008). The V166I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.The variant is found in MITONUC-MITOP panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Pathogenic	0.19
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.59	D;D;D;T;T
Eigen	Benign	-0.047
Eigen_PC	Benign	0.041
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.20	T;T;T;T;T
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Benign	1.5	L;L;L;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.68	N;N;N;N;.
REVEL	Uncertain	0.56
Sift	Benign	0.16	T;T;T;T;.
Sift4G	Benign	0.14	T;T;T;T;T
Polyphen		0.23	B;B;B;.;.
Vest4		0.62
MVP		0.84
MPC		0.92
ClinPred		0.017	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs147697454; hg19: chr11-66638660; COSMIC: COSV63082457; COSMIC: COSV63082457;