rs770734793

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_000098.3(CPT2):​c.1429C>T​(p.Arg477Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,613,948 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R477Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

CPT2
NM_000098.3 missense

Scores

8
9
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 0.815
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 Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.887

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CPT2NM_000098.3 linkc.1429C>T p.Arg477Trp missense_variant Exon 4 of 5 ENST00000371486.4 NP_000089.1 P23786A0A140VK13
CPT2NM_001330589.2 linkc.1429C>T p.Arg477Trp missense_variant Exon 4 of 5 NP_001317518.1 A0A1B0GTB8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CPT2ENST00000371486.4 linkc.1429C>T p.Arg477Trp missense_variant Exon 4 of 5 1 NM_000098.3 ENSP00000360541.3 P23786

Frequencies

GnomAD3 genomes
AF:
0.0000328
AC:
5
AN:
152226
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
250864
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135670
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000882
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000335
AC:
49
AN:
1461722
Hom.:
0
Cov.:
34
AF XY:
0.0000358
AC XY:
26
AN XY:
727158
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000414
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000328
AC:
5
AN:
152226
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74360
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000151
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.000109
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Carnitine palmitoyltransferase II deficiency Uncertain:2
Aug 16, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 477 of the CPT2 protein (p.Arg477Trp). This variant is present in population databases (rs770734793, gnomAD 0.005%). This missense change has been observed in individuals with CTP2 deficiency (PMID: 29552494, 31372341). ClinVar contains an entry for this variant (Variation ID: 577988). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CPT2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Sep 16, 2020
Natera, Inc.
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Carnitine palmitoyl transferase II deficiency, neonatal form Uncertain:1
Apr 11, 2023
Genome-Nilou Lab
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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
Apr 04, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Carnitine palmitoyl transferase II deficiency, myopathic form Uncertain:1
Apr 11, 2023
Genome-Nilou Lab
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Encephalopathy, acute, infection-induced, susceptibility to, 4 Uncertain:1
Apr 11, 2023
Genome-Nilou Lab
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Carnitine palmitoyl transferase II deficiency, severe infantile form Uncertain:1
Apr 11, 2023
Genome-Nilou Lab
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
BayesDel_addAF
Uncertain
0.14
D
BayesDel_noAF
Uncertain
0.13
CADD
Uncertain
25
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.80
D;.;.;T;T
Eigen
Uncertain
0.53
Eigen_PC
Uncertain
0.39
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Pathogenic
0.98
D;D;D;D;D
M_CAP
Uncertain
0.20
D
MetaRNN
Pathogenic
0.89
D;D;D;D;D
MetaSVM
Pathogenic
0.95
D
MutationAssessor
Pathogenic
3.6
H;.;.;.;.
PrimateAI
Uncertain
0.65
T
PROVEAN
Pathogenic
-4.7
D;.;.;.;.
REVEL
Pathogenic
0.71
Sift
Uncertain
0.013
D;.;.;.;.
Sift4G
Uncertain
0.017
D;.;.;.;.
Polyphen
1.0
D;.;.;.;.
Vest4
0.86
MutPred
0.76
Loss of methylation at R477 (P = 0.0677);Loss of methylation at R477 (P = 0.0677);Loss of methylation at R477 (P = 0.0677);Loss of methylation at R477 (P = 0.0677);Loss of methylation at R477 (P = 0.0677);
MVP
1.0
MPC
0.55
ClinPred
0.98
D
GERP RS
2.9
Varity_R
0.60
gMVP
0.76

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: rs770734793; hg19: chr1-53676775; COSMIC: COSV53760213; COSMIC: COSV53760213; API