rs144658100
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_ModerateBP6BS2_Supporting
The NM_000098.3(CPT2):āc.1025T>Cā(p.Met342Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00105 in 1,614,218 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: š 0.0011 ( 0 hom., cov: 32)
Exomes š: 0.0010 ( 2 hom. )
Consequence
CPT2
NM_000098.3 missense
NM_000098.3 missense
Scores
5
11
3
Clinical Significance
Conservation
PhyloP100: 8.02
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 Likely_benign. Variant got -4 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.111558825).
BP6
Variant 1-53210699-T-C is Benign according to our data. Variant chr1-53210699-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 376799.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=9}.
BS2
High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CPT2 | NM_000098.3 | c.1025T>C | p.Met342Thr | missense_variant | 4/5 | ENST00000371486.4 | NP_000089.1 | |
CPT2 | NM_001330589.2 | c.1025T>C | p.Met342Thr | missense_variant | 4/5 | NP_001317518.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CPT2 | ENST00000371486.4 | c.1025T>C | p.Met342Thr | missense_variant | 4/5 | 1 | NM_000098.3 | ENSP00000360541 | P1 | |
ENST00000629810.1 | n.286-290A>G | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes AF: 0.00107 AC: 163AN: 152222Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00104 AC: 261AN: 251094Hom.: 0 AF XY: 0.000936 AC XY: 127AN XY: 135712
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GnomAD4 exome AF: 0.00104 AC: 1525AN: 1461878Hom.: 2 Cov.: 31 AF XY: 0.00102 AC XY: 745AN XY: 727238
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GnomAD4 genome AF: 0.00107 AC: 163AN: 152340Hom.: 0 Cov.: 32 AF XY: 0.00102 AC XY: 76AN XY: 74492
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:10Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Jan 31, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 02, 2023 | Reported in trans with a second variant in CPT2 in an infant with a complex phenotype including Tetraology of Fallot, Meckels diverticulum, micro vesicular steatosis and hypotrophy of liver, mild s-shaped scoliosis with right thoracic convexity, hypotonia and hypoxemic spells (Josifovska et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24503134, 29429925, 28492532) - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 21, 2022 | The CPT2 1025T>C; p.Met342Thr variant (rs144658100) is reported in the literature in an individual affected with a dyslipidemia, but without clear disease association (Johansen 2014). This variant is also reported in ClinVar (Variation ID: 376799), and is found in the general population with an overall allele frequency of 0.11% (321/282498 alleles) in the Genome Aggregation Database. The methionine at codon 342 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.847). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Johansen CT et al. LipidSeq: a next-generation clinical resequencing panel for monogenic dyslipidemias. J Lipid Res. 2014 Apr;55(4):765-72. PMID: 24503134. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 29, 2021 | - - |
Carnitine palmitoyltransferase II deficiency Uncertain:2Benign:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Dec 30, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
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. - |
Carnitine palmitoyl transferase II deficiency, myopathic form;C1833511:Carnitine palmitoyl transferase II deficiency, severe infantile form;C1833518:Carnitine palmitoyl transferase II deficiency, neonatal form;C3280160:Encephalopathy, acute, infection-induced, susceptibility to, 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 22, 2021 | The c.1025T>C (p.M342T) alteration is located in exon 4 (coding exon 4) of the CPT2 gene. This alteration results from a T to C substitution at nucleotide position 1025, causing the methionine (M) at amino acid position 342 to be replaced by a threonine (T). The p.M342T alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Carnitine palmitoyl transferase II deficiency, myopathic form Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Mar 24, 2022 | - - |
Carnitine palmitoyl transferase II deficiency, severe infantile form Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | May 26, 2017 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 18, 2023 | Variant summary: CPT2 c.1025T>C (p.Met342Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.001 in 251094 control chromosomes, predominantly at a frequency of 0.0023 within the Finnish European subpopulation in the gnomAD database. In addition, the variant was found with even higher in certain European subpopulations, including the Estonian (0.007654), and Bulgarian (0.007121). These subpopulation frequencies are significantly higher than estimated maximum expected for a pathogenic variant in CPT2 causing Carnitine Palmitoyltransferase II Deficiency (0.0016), suggesting that the variant might be benign. To our knowledge, no occurrence of c.1025T>C in individuals affected with Carnitine Palmitoyltransferase II Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=9) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign. - |
CPT2-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 07, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;.;.;T;T
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.;.;.;.
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.;.;.;.
REVEL
Pathogenic
Sift
Uncertain
D;.;.;.;.
Sift4G
Benign
T;.;.;.;.
Polyphen
D;.;.;.;.
Vest4
MVP
MPC
ClinPred
T
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