rs397509431
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000098.3(CPT2):c.1239_1240delGA(p.Lys414fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000119 in 1,614,088 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00012 ( 0 hom. )
Consequence
CPT2
NM_000098.3 frameshift
NM_000098.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.39
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 Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-53210911-CAG-C is Pathogenic according to our data. Variant chr1-53210911-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 92430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CPT2 | NM_000098.3 | c.1239_1240delGA | p.Lys414fs | frameshift_variant | 4/5 | ENST00000371486.4 | NP_000089.1 | |
| CPT2 | NM_001330589.2 | c.1239_1240delGA | p.Lys414fs | frameshift_variant | 4/5 | NP_001317518.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CPT2 | ENST00000371486.4 | c.1239_1240delGA | p.Lys414fs | frameshift_variant | 4/5 | 1 | NM_000098.3 | ENSP00000360541.3 |
Frequencies
GnomAD3 genomes 0.000105 AC: 16AN: 152200Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000211 AC: 53AN: 251372Hom.: 0 AF XY: 0.000155 AC XY: 21AN XY: 135876
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GnomAD4 exome AF: 0.000120 AC: 176AN: 1461888Hom.: 0 AF XY: 0.000106 AC XY: 77AN XY: 727248
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GnomAD4 genome 0.000105 AC: 16AN: 152200Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74346
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:13Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Carnitine palmitoyltransferase II deficiency Pathogenic:3Other:2
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 10, 2016 | Variant summary: The CPT2 c.1239_1240delGA (p.Lys414Thrfs) variant results in a premature termination codon, predicted to cause a truncated or absent CPT2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 13/121214 (1/9328), which does not exceed the estimated maximal expected allele frequency for a pathogenic CPT2 variant of 1/9328 (0.0015811). The variant of interest has been reported in multiple affected individuals via publications and has been indicated to be a part of a complex allele with another pathogenic CPT2 variant, p.F448L in multiple affected individuals. In addition, multiple clinical laboratories/databases cite the variant as "pathogenic." Therefore, taking all available lines of evidence, the variant of interest is classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | This sequence change creates a premature translational stop signal (p.Lys414Thrfs*7) 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 (rs397509431, gnomAD 0.5%). This premature translational stop signal has been observed in individual(s) with CPT2-deficiency, and has been observed to occur in cis with the p.Phe448Leu missense change (PMID: 10090476, 12673791, 12707442, 21913903). This variant is also known as c.del1238_1239AG/Q413fs. ClinVar contains an entry for this variant (Variation ID: 92430). For these reasons, this variant has been classified as Pathogenic. - |
| not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Pathogenic 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. - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
not provided Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 10, 2024 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Also known as 413delAG, 1237delAG and c.del1238_1239AG; This variant is associated with the following publications: (PMID: 22975760, 25827434, 19335026, 28871440, 31428121, 11477613, 10090476, 21913903, 34958143, 30476936, 36696737) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 21, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 25, 2012 | - - |
Carnitine palmitoyl transferase II deficiency, myopathic form Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Oct 26, 2020 | This sequence change is a deletion of 2 bp in exon 4 (of 5) of CPT2 that is predicted to create a premature termination codon at position 420 (p.(Lys414Thrfs*7)). It is expected to result in nonsense mediated decay, in a gene where loss of function is an established mechanism of disease (ClinVar). The variant is present in a large population cohort at a frequency of 0.02%, which is consistent with recessive disease (rs397509431, 53/251,372 alleles, 0 homozygotes in gnomAD v2.1). It is more common in the Ashkenazi Jewish population at a frequency of 0.5% (47/10,080 alleles in gnomAD v2.1). The variant is the second most commonly occurring pathogenic variant in Europeans, always in cis with NM_000098.3:c.1342T>C, p.Phe448Leu (PMID: 20301431). The variant has been identified in the homozygous state and with a second pathogenic allele in multiple cases with phenotypes ranging from the lethal neonatal, infantile, and myopathic forms of CPT II deficiency, and segregates with disease in at least one family (PMID: 10090476, 11477613, 12410208). CPT II deficiency has been demonstrated in patient cells from homozygous cases, including both enzyme activity and long-chain fatty-acid oxidation (PMID: 11477613). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM3_VeryStrong, PM2, PP1, PP4. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 06, 2021 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with neonatal, infantile and stress-induced myopathic CPT II deficiency. (I) 0106 - This gene is associated with autosomal recessive disease. This gene is generally considered to be associated with an autosomal recessive condition, but some cases of manifesting carriers have been reported for the myopathic of CPT II deficiency (PMID: 32295037). (I) 0115 - Variants in this gene are known to have variable expressivity. The myopathic form of this condition can manifest from infancy to adulthood and variable onset, frequency, and severity of symptoms have been reported (PMID: 32295037). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2) (53 heterozygotes, 0 homozygotes) and is enriched in the Ashkenazi Jewish sub-population. (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Other variants predicted to cause NMD have been reported as pathogenic in individuals with CPT II deficiency (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with the myopathic form of CPT II deficiency (ClinVar, PMID: 21913903). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Carnitine palmitoyl transferase II deficiency, severe infantile form Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 19, 2019 | NM_000098.2(CPT2):c.1239_1240delGA(K414Tfs*7) is classified as pathogenic in the context of carnitine palmitoyltransferase II deficiency and is associated with the neonatal form of disease. Sources cited for classification include the following: PMID 12673791, 16996287, 10090476‚Äé, 18550408 and 15642848. Classification of NM_000098.2(CPT2):c.1239_1240delGA(K414Tfs*7) 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, 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 03, 2022 | - - |
Encephalopathy, acute, infection-induced, susceptibility to, 4 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 29, 2024 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at