rs147697454
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM1BP4_ModerateBS1_SupportingBS2
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
Consequence
NM_001040716.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
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
Frequencies
GnomAD3 genomes AF: 0.000585 AC: 89AN: 152204Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000471 AC: 118AN: 250760Hom.: 0 AF XY: 0.000472 AC XY: 64AN XY: 135478
GnomAD4 exome AF: 0.000840 AC: 1227AN: 1460736Hom.: 2 Cov.: 33 AF XY: 0.000782 AC XY: 568AN XY: 726444
GnomAD4 genome AF: 0.000584 AC: 89AN: 152322Hom.: 0 Cov.: 32 AF XY: 0.000631 AC XY: 47AN XY: 74472
ClinVar
Submissions by phenotype
Pyruvate carboxylase deficiency Uncertain:2Benign:1
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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. -
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not specified Uncertain:1
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
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
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at