rs74315297
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_000098.3(CPT2):c.1342T>C(p.Phe448Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000118 in 1,614,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,other (no stars).
Frequency
Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00012 ( 0 hom. )
Consequence
CPT2
NM_000098.3 missense
NM_000098.3 missense
Scores
11
6
2
Clinical Significance
Conservation
PhyloP100: 7.67
Genes affected
CPT2 (HGNC:2330): (carnitine palmitoyltransferase 2) The protein encoded by this gene is a nuclear protein which is transported to the mitochondrial inner membrane. Together with carnitine palmitoyltransferase I, the encoded protein oxidizes long-chain fatty acids in the mitochondria. Defects in this gene are associated with mitochondrial long-chain fatty-acid (LCFA) oxidation disorders. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.759
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CPT2 | NM_000098.3 | c.1342T>C | p.Phe448Leu | missense_variant | 4/5 | ENST00000371486.4 | |
CPT2 | NM_001330589.2 | c.1342T>C | p.Phe448Leu | missense_variant | 4/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CPT2 | ENST00000371486.4 | c.1342T>C | p.Phe448Leu | missense_variant | 4/5 | 1 | NM_000098.3 | P1 | |
ENST00000629810.1 | n.286-607A>G | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000105 AC: 16AN: 152164Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000211 AC: 53AN: 251382Hom.: 0 AF XY: 0.000155 AC XY: 21AN XY: 135882
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GnomAD4 exome AF: 0.000119 AC: 174AN: 1461892Hom.: 0 Cov.: 34 AF XY: 0.000103 AC XY: 75AN XY: 727248
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GnomAD4 genome ? AF: 0.000105 AC: 16AN: 152164Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74336
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ClinVar
Significance: Conflicting classifications of pathogenicity; other
Submissions summary: Uncertain:3Benign:1Other:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Carnitine palmitoyltransferase II deficiency Uncertain:2Other:1
not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Uncertain significance and reported on 06-11-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 448 of the CPT2 protein (p.Phe448Leu). This variant is present in population databases (rs74315297, gnomAD 0.5%). This missense change has been observed in individual(s) with autosomal recessive carnitine palmitoyltransferase II deficiency. It is often reported in cis with the truncating variant c.1239_1240del (p.Lys414Thrfs*7), and this haplotype is a common cause of CPT2-deficiency (PMID: 10090476, 12673791, 12707442, 21913903). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 8960). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CPT2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, no assertion criteria provided | literature only | GeneReviews | Mar 16, 2017 | - - |
Carnitine palmitoyl transferase II deficiency, myopathic form;C1833511:Carnitine palmitoyl transferase II deficiency, severe infantile form;C1833518:Carnitine palmitoyl transferase II deficiency, neonatal form Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Oct 27, 2021 | NM_000098.2(CPT2):c.1342T>C(F448L) is a missense variant classified as a variant of uncertain significance in the context of carnitine palmitoyltransferase II deficiency. F448L has been observed in cases with relevant disease (PMID: 12673791). Functional assessments of this variant are not available in the literature. F448L has been observed in population frequency databases (gnomAD: ASJ 0.49%). In summary, there is insufficient evidence to classify NM_000098.2(CPT2):c.1342T>C(F448L) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 08, 2015 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
not provided Other:1
other, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 02, 2015 | - Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles). |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Uncertain
D;.;.;T;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T;T;T;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;.;.;.;.
MutationTaster
Benign
A
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.;.;.;.
REVEL
Pathogenic
Sift
Uncertain
D;.;.;.;.
Sift4G
Uncertain
D;.;.;.;.
Polyphen
D;.;.;.;.
Vest4
MutPred
Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at