rs147697454

Variant names:

• chr11-66871189-C-T
• rs147697454
• NM_001040716.2:c.496G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM1 BP4_Moderate BS1_Supporting BS2

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

Our verdict: Likely_benign. The variant received -5 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
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PC	NM_001040716.2	c.496G>A	p.Val166Ile	missense_variant	Exon 7 of 23	ENST00000393960.7	NP_001035806.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PC	ENST00000393960.7	c.496G>A	p.Val166Ile	missense_variant	Exon 7 of 23	5	NM_001040716.2	ENSP00000377532.1

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

GnomAD2 exomes AF: 0.000471 AC: 118 AN: 250760 AF XY: 0.000472

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 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 AC: 5 AN: 33466

Gnomad4 AMR exome AF: 0.000717 AC: 32 AN: 44658

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26082

Gnomad4 EAS exome AF: 0.0000252 AC: 1 AN: 39652

Gnomad4 SAS exome AF: 0.0000116 AC: 1 AN: 86176

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53360

Gnomad4 NFE exome AF: 0.00102 AC: 1134 AN: 1111252

Gnomad4 Remaining exome AF: 0.000895 AC: 54 AN: 60330

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 AC: 0.000384967 AN: 0.000384967

Gnomad4 AMR AF: 0.00157 AC: 0.0015676 AN: 0.0015676

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000706 AC: 0.000705613 AN: 0.000705613

Gnomad4 OTH AF: 0.000473 AC: 0.000473037 AN: 0.000473037

Alfa AF: 0.000675 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

Nov 08, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Oct 01, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 at a homozygous state in at-least one individual affected with Pyruvate Carboxylase Deficiency without strong evidence of causality (Wang_2008). Another homozygous missense VUS variant and a heterozygous pathogenic change (PC c.1892G>A, p.Arg631Gln) were also identified in this patient. This report does not provide unequivocal conclusions about association of the variant with Pyruvate Carboxylase Deficiency. 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). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 203919). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases Uncertain:1

Feb 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 14, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in homozygous state in a patient in published literature (PMID: 18676167) with pyruvate carboxylase deficiency who was homozygous for V166I and homozygous for another missense change in the PC gene that results in a more severe amino acid substitution; This variant is associated with the following publications: (PMID: 19026585, 34426522, 18676167) -

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
LIST_S2	Pathogenic	0.98	.;.;D;.;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;.;.
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
Mutation Taster		=4/96	disease causing

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;