rs17848485

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 3P and 6B. PM1PP3BP4_StrongBP6BS2_Supporting

The NM_000098.3(CPT2):c.1634A>C(p.Glu545Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000866 in 1,605,740 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 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. E545K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00071 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00088 ( 4 hom. )

Consequence

CPT2
NM_000098.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:3

Conservation

PhyloP100: 9.32

Publications

12 publications found

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 Gene-Disease associations (from GenCC):

carnitine palmitoyltransferase II deficiency
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Myriad Women’s Health
carnitine palmitoyl transferase II deficiency, myopathic form
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia
carnitine palmitoyl transferase II deficiency, neonatal form
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia
carnitine palmitoyl transferase II deficiency, severe infantile form
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet
encephalopathy, acute, infection-induced, susceptibility to, 4
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

CPT2 links:

ENSG00000236723 (HGNC:):

ENSG00000236723 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000098.3

PP3

Multiple lines of computational evidence support a deleterious effect 6: BayesDel_noAF, Eigen, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.02558583).

BP6

Variant 1-53211308-A-C is Benign according to our data. Variant chr1-53211308-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 166955.

BS2

High Homozygotes in GnomAdExome4 at 4 AR,Unknown 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 rank	MANE	Protein	UniProt
CPT2	NM_000098.3 link	c.1634A>C	p.Glu545Ala	missense_variant	Exon 4 of 5	ENST00000371486.4	NP_000089.1
CPT2	NM_001330589.2 link	c.1576+58A>C		intron_variant	Intron 4 of 4		NP_001317518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPT2	ENST00000371486.4 link	c.1634A>C	p.Glu545Ala	missense_variant	Exon 4 of 5	1	NM_000098.3	ENSP00000360541.3

Frequencies

GnomAD3 genomes

AF:

0.000710

AC:

108

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000458

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00154

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00273

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000632

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.000803

AC:

187

AN:

232770

AF XY:

0.000786

show subpopulations

Gnomad AFR exome

AF:

0.000481

Gnomad AMR exome

AF:

0.000759

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000935

Gnomad FIN exome

AF:

0.00262

Gnomad NFE exome

AF:

0.000665

Gnomad OTH exome

AF:

0.000519

GnomAD4 exome

AF:

0.000882

AC:

1282

AN:

1453420

Hom.:

Cov.:

AF XY:

0.000867

AC XY:

626

AN XY:

722326

show subpopulations

African (AFR)

AF:

0.000602

AC:

AN:

33248

American (AMR)

AF:

0.000757

AC:

AN:

43608

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25920

East Asian (EAS)

AF:

0.00314

AC:

123

AN:

39180

South Asian (SAS)

AF:

0.000413

AC:

AN:

84814

European-Finnish (FIN)

AF:

0.00237

AC:

125

AN:

52648

Middle Eastern (MID)

AF:

0.000869

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.000819

AC:

908

AN:

1108168

Other (OTH)

AF:

0.000549

AC:

AN:

60080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

134

202

269

336

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

132

176

220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000709

AC:

108

AN:

152320

Hom.:

Cov.:

AF XY:

0.000765

AC XY:

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.000457

AC:

AN:

41572

American (AMR)

AF:

0.000327

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00154

AC:

AN:

5180

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00273

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000632

AC:

AN:

68018

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000733

Hom.:

Bravo

AF:

0.000521

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000684

AC:

ESP6500EA

AF:

0.000701

AC:

ExAC

AF:

0.000726

AC:

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:5

Apr 11, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 07, 2023

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 14, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP3 -

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 01, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported as heterozygous in an asymptomatic infant with a positive newborn screen for CPT2 deficiency where another variant in CPT2 was not detected (Tajima et al., 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29429925, 26636822, 24503134, 20952238, 28074886, 28801073) -

Carnitine palmitoyltransferase II deficiency

Benign:2

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Carnitine palmitoyl transferase II deficiency, severe infantile form

Uncertain:1

Sep 14, 2017

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

CPT2-related disorder

Benign:1

Nov 28, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This 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

Uncertain

0.37

BayesDel_addAF

Uncertain

0.090

BayesDel_noAF

Pathogenic

0.29

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

D;.;T

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.84

T;T;T

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.026

T;T;T

MetaSVM

Uncertain

0.50

MutationAssessor

Uncertain

2.1

M;.;.

PhyloP100

9.3

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-5.3

D;.;.

REVEL

Pathogenic

0.83

Sift

Uncertain

0.0020

D;.;.

Sift4G

Uncertain

0.0040

D;.;.

Polyphen

1.0

D;.;.

Vest4

0.80

MVP

1.0

MPC

0.57

ClinPred

0.085

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.83

gMVP

0.74

Mutation Taster

=16/84

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over