1-53210044-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000098.3(CPT2):c.370C>T(p.Arg124*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,602 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R124R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000098.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CPT2 | NM_000098.3 | c.370C>T | p.Arg124* | stop_gained | 4/5 | ENST00000371486.4 | NP_000089.1 | |
CPT2 | NM_001330589.2 | c.370C>T | p.Arg124* | stop_gained | 4/5 | NP_001317518.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000659 AC: 1AN: 151762Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251336Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135902
GnomAD4 exome AF: 0.0000150 AC: 22AN: 1461840Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13AN XY: 727222
GnomAD4 genome AF: 0.00000659 AC: 1AN: 151762Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74072
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 06, 2018 | The R124X nonsense pathogenic variant in the CPT2 gene has been reported previously in association with carnitine palmitoyltransferase II (CPT2) deficiency (Yang et al., 1998). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant is found in CPT2 panel(s). - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Oct 02, 2017 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Carnitine palmitoyltransferase II deficiency Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 29, 2021 | Variant summary: CPT2 c.370C>T (p.Arg124X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 251336 control chromosomes (gnomAD). c.370C>T has been reported in the literature in compound heterozygous individuals affected with adult-onset Carnitine Palmitoyltransferase II Deficiency (Yang_1998, Isackson_2006), while it has also been reported in a homozygous individual with lethal neonatal form of the disease (McGill_2012). These data indicate that the variant is likely to be associated with disease. Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 15, 2023 | ClinVar contains an entry for this variant (Variation ID: 203659). This sequence change creates a premature translational stop signal (p.Arg124*) in the CPT2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CPT2 are known to be pathogenic (PMID: 16781677, 16996287). This variant is present in population databases (rs201065226, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with carnitine palmitoyltransferase II deficiency (PMID: 9562964, 16996287, 22652984). For these reasons, this variant has been classified as Pathogenic. - |
Carnitine palmitoyl transferase II deficiency, severe infantile form Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 11, 2019 | NM_000098.2(CPT2):c.370C>T(R124*) is classified as pathogenic in the context of carnitine palmitoyltransferase II deficiency. Sources cited for classification include the following: PMID 16996287, 23322164 and 9562964. Classification of NM_000098.2(CPT2):c.370C>T(R124*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. - |
Carnitine palmitoyl transferase II deficiency, neonatal form Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Dec 21, 2015 | - - |
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 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 08, 2024 | - - |
Carnitine palmitoyl transferase II deficiency, myopathic form Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Dec 21, 2015 | - - |
Encephalopathy, acute, infection-induced, susceptibility to, 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 14, 2024 | - - |
Carnitine palmitoyl transferase II deficiency, severe infantile form;C1833518:Carnitine palmitoyl transferase II deficiency, neonatal form Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at