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

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

CPT2
NM_000098.3 stop_gained

Scores

5
1
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 7.57
Variant links:
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]

Genome browser will be placed here

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 1-53210044-C-T is Pathogenic according to our data. Variant chr1-53210044-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 203659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-53210044-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CPT2NM_000098.3 linkc.370C>T p.Arg124* stop_gained 4/5 ENST00000371486.4 NP_000089.1 P23786A0A140VK13
CPT2NM_001330589.2 linkc.370C>T p.Arg124* stop_gained 4/5 NP_001317518.1 A0A1B0GTB8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CPT2ENST00000371486.4 linkc.370C>T p.Arg124* stop_gained 4/51 NM_000098.3 ENSP00000360541.3 P23786

Frequencies

GnomAD3 genomes
AF:
0.00000659
AC:
1
AN:
151762
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251336
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135902
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000150
AC:
22
AN:
1461840
Hom.:
0
Cov.:
31
AF XY:
0.0000179
AC XY:
13
AN XY:
727222
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000171
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000659
AC:
1
AN:
151762
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74072
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000450
Hom.:
0
Bravo
AF:
0.0000151

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:14
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:4
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxNov 06, 2018The 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 submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsOct 02, 2017- -
Pathogenic, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Carnitine palmitoyltransferase II deficiency Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJan 29, 2021Variant 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 providedclinical testingNatera, Inc.Sep 16, 2020- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 15, 2023ClinVar 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 submitterclinical testingGenome-Nilou LabApr 11, 2023- -
Pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Dec 11, 2019NM_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 submitterclinical testingCounsylDec 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 submitterclinical testingFulgent Genetics, Fulgent GeneticsMay 08, 2024- -
Carnitine palmitoyl transferase II deficiency, myopathic form Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingCounsylDec 21, 2015- -
Encephalopathy, acute, infection-induced, susceptibility to, 4 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsFeb 14, 2024- -
Carnitine palmitoyl transferase II deficiency, severe infantile form;C1833518:Carnitine palmitoyl transferase II deficiency, neonatal form Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBaylor Genetics-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.66
CADD
Pathogenic
37
DANN
Uncertain
1.0
Eigen
Pathogenic
0.99
Eigen_PC
Pathogenic
0.88
FATHMM_MKL
Pathogenic
0.99
D
Vest4
0.90
GERP RS
5.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs201065226; hg19: chr1-53675716; API