rs74315295

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_000098.3(CPT2):c.1148T>A(p.Phe383Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,614,040 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

CPT2
NM_000098.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15O:1

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]

CPT2 links:

ENSG00000236723 (HGNC:):

ENSG00000236723 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-53210822-T-A is Pathogenic according to our data. Variant chr1-53210822-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8958.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-53210822-T-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPT2	NM_000098.3 link	c.1148T>A	p.Phe383Tyr	missense_variant	Exon 4 of 5	ENST00000371486.4	NP_000089.1	P23786A0A140VK13
CPT2	NM_001330589.2 link	c.1148T>A	p.Phe383Tyr	missense_variant	Exon 4 of 5		NP_001317518.1	A0A1B0GTB8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPT2	ENST00000371486.4 link	c.1148T>A	p.Phe383Tyr	missense_variant	Exon 4 of 5	1	NM_000098.3	ENSP00000360541.3		P23786

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152152

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:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251350

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135856

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Carnitine palmitoyl transferase II deficiency, severe infantile form

Pathogenic:4

Apr 11, 2023

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 28, 2020

Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 30, 2015

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 21, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Carnitine palmitoyltransferase II deficiency

Pathogenic:3Other:1

Aug 09, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Across a selection of the available literature, the CPT2 c.1148T>A (p.Phe383Tyr) missense variant has been reported in a total of nine individuals with carnitine palmitoyltransferase II (CPT II) deficiency, including in seven with the infantile-onset hepatocardiomuscular form and in two with adult-onset myopathic form (Yamamoto et al. 1998; Wataya et al. 1998; Yasuno et al. 2008). Of those presenting with the hepatocardiomuscular form, one was homozygous for the p.Phe383Tyr variant, three, including two siblings, were compound heterozygous for the variant and a second missense variant, and three were heterozygous with no second variant identified. Of those presenting with the myopathic form, one was homozygous for the p.Phe383Tyr variant and one was heterozygous with no second variant identified. The p.Phe383Tyr variant was also detected in a heterozygous state in three healthy parents of individuals with CPT II. The p.Phe383Tyr variant was absent from 80 Japanese controls and is reported at a frequency of 0.00035 in the East Asian population of the Exome Aggregation Consortium. Transient expression of the p.Phe383Tyr variant in COS-1 cells revealed an intermediate level of CPT II enzyme activity at approximately 34% of normal, while very low activity was detected, approximately 10% of normal, when the variant was co-expressed with a second missense variant (Wataya et al. 1998). Based on the collective evidence, the p.Phe383Tyr variant is classified as pathogenic for carnitine palmitoyltransferase II deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Nov 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with tyrosine, which is neutral and polar, at codon 383 of the CPT2 protein (p.Phe383Tyr). This variant is present in population databases (rs74315295, gnomAD 0.03%). This missense change has been observed in individual(s) with CPT2 deficiency and CPT2 specific enzyme activity <35% of normal (PMID: 9600456, 18363739, 23700290, 28516040). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8958). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CPT2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects CPT2 function (PMID: 9600456). For these reasons, this variant has been classified as Pathogenic. -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jul 22, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

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

Pathogenic:2

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PP3+PM3_VeryStrong -

Jul 28, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Carnitine palmitoyl transferase II deficiency, myopathic form

Pathogenic:2

Nov 30, 2015

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 21, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Carnitine palmitoyl transferase II deficiency, neonatal form

Pathogenic:1

Nov 30, 2015

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Seizure;C0497552:Abnormality of the nervous system

Pathogenic:1

May 18, 2016

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Pathogenic:1

Feb 13, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Carnitine palmitoyl transferase II deficiency, severe infantile form;C1833518:Carnitine palmitoyl transferase II deficiency, neonatal form

Pathogenic:1

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Uncertain

0.096

BayesDel_noAF

Pathogenic

0.20

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.32

T;.;.;T;T

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.84

T;T;T;T;T

M_CAP

Benign

0.039

MetaRNN

Uncertain

0.70

D;D;D;D;D

MetaSVM

Uncertain

0.35

MutationAssessor

Benign

1.5

L;.;.;.;.

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.89

N;.;.;.;.

REVEL

Pathogenic

0.76

Sift

Benign

0.61

T;.;.;.;.

Sift4G

Benign

0.63

T;.;.;.;.

Polyphen

0.83

P;.;.;.;.

Vest4

0.61

MVP

1.0

MPC

0.19

ClinPred

0.24

GERP RS

4.7

Varity_R

0.37

gMVP

0.53

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