rs373638740

Positions:

chr1-53210365-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

The ENST00000371486.4(CPT2):c.691C>T(p.Arg231Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000147 in 1,613,984 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R231Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

CPT2
ENST00000371486.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:4

Conservation

PhyloP100: 0.465

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]

CPT2 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-53210365-C-T is Pathogenic according to our data. Variant chr1-53210365-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 203661.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=2, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPT2	NM_000098.3 linkuse as main transcript	c.691C>T	p.Arg231Trp	missense_variant	4/5	ENST00000371486.4	NP_000089.1
CPT2	NM_001330589.2 linkuse as main transcript	c.691C>T	p.Arg231Trp	missense_variant	4/5		NP_001317518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPT2	ENST00000371486.4 linkuse as main transcript	c.691C>T	p.Arg231Trp	missense_variant	4/5	1	NM_000098.3	ENSP00000360541	P1
	ENST00000629810.1 linkuse as main transcript	n.330G>A		non_coding_transcript_exon_variant	2/3	5

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000359

AC:

AN:

250840

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

135658

show subpopulations

Gnomad AFR exome

AF:

0.0000617

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:

0.0000618

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000159

AC:

232

AN:

1461810

Hom.:

Cov.:

AF XY:

0.000140

AC XY:

102

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

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:

0.000203

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000103

Hom.:

Bravo

AF:

0.0000453

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Carnitine palmitoyltransferase II deficiency

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 231 of the CPT2 protein (p.Arg231Trp). This variant is present in population databases (rs373638740, gnomAD 0.006%). This missense change has been observed in individuals with carnitine palmitoyltransferase II deficiency and/or CPT2-related conditions (PMID: 16996287, 24398345, 24602495, 30455135). ClinVar contains an entry for this variant (Variation ID: 203661). 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 expected to disrupt CPT2 protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided

Pathogenic:1Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 01, 2021	- -

CPT2-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 24, 2024

The CPT2 c.691C>T variant is predicted to result in the amino acid substitution p.Arg231Trp. This variant has been reported with a second CPT2 variant in individuals with carnitine palmitoyltransferase II deficiency; however, pathogenicity was not established (Isackson et al. 2006. PubMed ID: 16996287; Table 4, Joshi et al. 2013. PubMed ID: 24398345; Table 1, Lehmann and Zierz. 2014. PubMed ID: 24602495). This variant was observed in the compound heterozygous state with a nonsense CPT2 variant in an individual undergoing testing with a CPT2-related disease phenotype (Internal Data, PreventionGenetics). This variant is reported in 0.0062% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic. -

Encephalopathy, acute, infection-induced, susceptibility to, 4

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 25, 2024

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 12, 2023

Variant summary: CPT2 c.691C>T (p.Arg231Trp) results in a non-conservative amino acid change located in the Choline/carnitine acyltransferase domain of 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 3.6e-05 in 250840 control chromosomes. c.691C>T has been reported in the literature in individuals affected with Carnitine Palmitoyltransferase II Deficiency. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS n=4, pathogenic n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Carnitine palmitoyl transferase II deficiency, severe infantile form

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

May 18, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.15

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

D;.;.;T;T

Eigen

Uncertain

0.28

Eigen_PC

Benign

0.096

FATHMM_MKL

Benign

0.18

LIST_S2

Pathogenic

0.98

D;D;D;D;D

M_CAP

Uncertain

0.17

MetaRNN

Uncertain

0.63

D;D;D;D;D

MetaSVM

Uncertain

0.39

MutationAssessor

Pathogenic

3.4

M;.;.;.;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.26

PROVEAN

Pathogenic

-5.7

D;.;.;.;.

REVEL

Uncertain

0.51

Sift

Uncertain

0.0010

D;.;.;.;.

Sift4G

Pathogenic

0.0010

D;.;.;.;.

Polyphen

1.0

D;.;.;.;.

Vest4

0.54

MVP

0.99

MPC

0.54

ClinPred

0.85

GERP RS

3.6

Varity_R

0.81

gMVP

0.79

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over