rs144658100

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_ModerateBP6BS2_Supporting

The NM_000098.3(CPT2):ā€‹c.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

Scores

5
11
3

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:3

Conservation

PhyloP100: 8.02
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 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
CPT2NM_000098.3 linkuse as main transcriptc.1025T>C p.Met342Thr missense_variant 4/5 ENST00000371486.4 NP_000089.1
CPT2NM_001330589.2 linkuse as main transcriptc.1025T>C p.Met342Thr missense_variant 4/5 NP_001317518.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CPT2ENST00000371486.4 linkuse as main transcriptc.1025T>C p.Met342Thr missense_variant 4/51 NM_000098.3 ENSP00000360541 P1
ENST00000629810.1 linkuse as main transcriptn.286-290A>G intron_variant, non_coding_transcript_variant 5

Frequencies

GnomAD3 genomes
AF:
0.00107
AC:
163
AN:
152222
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000145
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000327
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00273
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00175
Gnomad OTH
AF:
0.00143
GnomAD3 exomes
AF:
0.00104
AC:
261
AN:
251094
Hom.:
0
AF XY:
0.000936
AC XY:
127
AN XY:
135712
show subpopulations
Gnomad AFR exome
AF:
0.000308
Gnomad AMR exome
AF:
0.000520
Gnomad ASJ exome
AF:
0.000198
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000294
Gnomad FIN exome
AF:
0.00231
Gnomad NFE exome
AF:
0.00149
Gnomad OTH exome
AF:
0.00130
GnomAD4 exome
AF:
0.00104
AC:
1525
AN:
1461878
Hom.:
2
Cov.:
31
AF XY:
0.00102
AC XY:
745
AN XY:
727238
show subpopulations
Gnomad4 AFR exome
AF:
0.000209
Gnomad4 AMR exome
AF:
0.000492
Gnomad4 ASJ exome
AF:
0.000115
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000313
Gnomad4 FIN exome
AF:
0.00251
Gnomad4 NFE exome
AF:
0.00114
Gnomad4 OTH exome
AF:
0.00101
GnomAD4 genome
AF:
0.00107
AC:
163
AN:
152340
Hom.:
0
Cov.:
32
AF XY:
0.00102
AC XY:
76
AN XY:
74492
show subpopulations
Gnomad4 AFR
AF:
0.000144
Gnomad4 AMR
AF:
0.000327
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00273
Gnomad4 NFE
AF:
0.00175
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.00132
Hom.:
1
Bravo
AF:
0.000895
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.00116
AC:
10
ExAC
AF:
0.00112
AC:
136
EpiCase
AF:
0.00142
EpiControl
AF:
0.00130

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 submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsJan 31, 2017- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxApr 02, 2023Reported 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 submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesOct 21, 2022The 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 submitterclinical testingMayo Clinic Laboratories, Mayo ClinicJun 29, 2021- -
Carnitine palmitoyltransferase II deficiency Uncertain:2Benign:1
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Dec 30, 2019- -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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 submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 22, 2021The 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 submitterclinical testingMGZ Medical Genetics CenterMar 24, 2022- -
Carnitine palmitoyl transferase II deficiency, severe infantile form Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCounsylMay 26, 2017- -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpSep 18, 2023Variant 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 providedclinical testingPreventionGenetics, part of Exact SciencesJul 07, 2022This 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.62
BayesDel_addAF
Uncertain
0.10
D
BayesDel_noAF
Pathogenic
0.37
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.63
D;.;.;T;T
Eigen
Pathogenic
0.70
Eigen_PC
Uncertain
0.65
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.90
D;D;D;D;D
M_CAP
Uncertain
0.12
D
MetaRNN
Benign
0.11
T;T;T;T;T
MetaSVM
Uncertain
0.63
D
MutationAssessor
Uncertain
2.3
M;.;.;.;.
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.66
T
PROVEAN
Uncertain
-3.4
D;.;.;.;.
REVEL
Pathogenic
0.85
Sift
Uncertain
0.022
D;.;.;.;.
Sift4G
Benign
0.17
T;.;.;.;.
Polyphen
0.99
D;.;.;.;.
Vest4
0.94
MVP
1.0
MPC
0.57
ClinPred
0.11
T
GERP RS
4.6
Varity_R
0.46
gMVP
0.75

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: rs144658100; hg19: chr1-53676371; API