1-53210039-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PM2BP4_Strong

The NM_000098.3(CPT2):​c.365C>T​(p.Ser122Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000195 in 1,613,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S122S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

CPT2
NM_000098.3 missense

Scores

9
10

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 2.11
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 0 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000098.3
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.014732182).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CPT2NM_000098.3 linkc.365C>T p.Ser122Phe missense_variant Exon 4 of 5 ENST00000371486.4 NP_000089.1 P23786A0A140VK13
CPT2NM_001330589.2 linkc.365C>T p.Ser122Phe 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.365C>T p.Ser122Phe missense_variant Exon 4 of 5 1 NM_000098.3 ENSP00000360541.3 P23786

Frequencies

GnomAD3 genomes
AF:
0.000197
AC:
30
AN:
151912
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000484
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00463
Gnomad SAS
AF:
0.000623
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000414
AC:
104
AN:
251266
Hom.:
0
AF XY:
0.000471
AC XY:
64
AN XY:
135904
show subpopulations
Gnomad AFR exome
AF:
0.0000621
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00348
Gnomad SAS exome
AF:
0.00121
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000194
AC:
284
AN:
1461816
Hom.:
0
Cov.:
31
AF XY:
0.000224
AC XY:
163
AN XY:
727200
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00385
Gnomad4 SAS exome
AF:
0.00125
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.000315
GnomAD4 genome
AF:
0.000197
AC:
30
AN:
152030
Hom.:
0
Cov.:
32
AF XY:
0.000175
AC XY:
13
AN XY:
74326
show subpopulations
Gnomad4 AFR
AF:
0.0000482
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00464
Gnomad4 SAS
AF:
0.000623
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000142
Hom.:
1
Bravo
AF:
0.000185
ExAC
AF:
0.000461
AC:
56
Asia WGS
AF:
0.00231
AC:
8
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:3
Jul 05, 2022
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Reported in a patient with acute necrotizing encephalopathy who also harbors a potentially disease-causing variant in the RANBP2 gene (Iyer et al., 2020); 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: 34426522, 26010953, 32102593) -

Nov 17, 2023
Revvity Omics, Revvity
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 01, 2021
CeGaT Center for Human Genetics Tuebingen
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Uncertain:1
Oct 13, 2016
Athena Diagnostics
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
Feb 26, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Carnitine palmitoyltransferase II deficiency Benign:1
Jan 28, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.21
BayesDel_addAF
Benign
-0.33
T
BayesDel_noAF
Benign
-0.25
CADD
Benign
20
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.77
D;.;.;T;T
Eigen
Benign
-0.058
Eigen_PC
Benign
0.023
FATHMM_MKL
Benign
0.73
D
LIST_S2
Uncertain
0.89
D;D;D;D;D
M_CAP
Benign
0.045
D
MetaRNN
Benign
0.015
T;T;T;T;T
MetaSVM
Uncertain
-0.13
T
MutationAssessor
Uncertain
2.7
M;.;.;.;.
PrimateAI
Benign
0.34
T
PROVEAN
Uncertain
-3.1
D;.;.;.;.
REVEL
Uncertain
0.36
Sift
Uncertain
0.025
D;.;.;.;.
Sift4G
Uncertain
0.038
D;.;.;.;.
Polyphen
0.018
B;.;.;.;.
Vest4
0.39
MVP
0.99
MPC
0.36
ClinPred
0.12
T
GERP RS
3.8
Varity_R
0.25
gMVP
0.42

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: rs192275019; hg19: chr1-53675711; COSMIC: COSV53759415; COSMIC: COSV53759415; API