rs75939866

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_000098.3(CPT2):c.302C>T(p.Ala101Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,614,132 control chromosomes in the GnomAD database, including 7 homozygotes. 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0061 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00073 ( 4 hom. )

Consequence

CPT2
NM_000098.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 2.65

Publications

10 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a topological_domain Mitochondrial matrix (size 152) in uniprot entity CPT2_HUMAN there are 13 pathogenic changes around while only 4 benign (76%) in NM_000098.3

BP4

Computational evidence support a benign effect (MetaRNN=0.009035051).

BP6

Variant 1-53202391-C-T is Benign according to our data. Variant chr1-53202391-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 137028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00611 (930/152316) while in subpopulation AFR AF = 0.0215 (893/41556). AF 95% confidence interval is 0.0203. There are 3 homozygotes in GnomAd4. There are 414 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPT2	NM_000098.3 link	c.302C>T	p.Ala101Val	missense_variant	Exon 3 of 5	ENST00000371486.4	NP_000089.1	P23786A0A140VK13
CPT2	NM_001330589.2 link	c.302C>T	p.Ala101Val	missense_variant	Exon 3 of 5		NP_001317518.1	A0A1B0GTB8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPT2	ENST00000371486.4 link	c.302C>T	p.Ala101Val	missense_variant	Exon 3 of 5	1	NM_000098.3	ENSP00000360541.3		P23786

Frequencies

GnomAD3 genomes

AF:

0.00610

AC:

929

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0215

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

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:

0.000250

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00155

AC:

389

AN:

251458

AF XY:

0.00118

show subpopulations

Gnomad AFR exome

AF:

0.0212

Gnomad AMR exome

AF:

0.000607

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000185

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000726

AC:

1061

AN:

1461816

Hom.:

Cov.:

AF XY:

0.000612

AC XY:

445

AN XY:

727210

show subpopulations

African (AFR)

AF:

0.0241

AC:

808

AN:

33478

American (AMR)

AF:

0.000760

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000121

AC:

135

AN:

1111948

Other (OTH)

AF:

0.00126

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

114

172

229

286

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00611

AC:

930

AN:

152316

Hom.:

Cov.:

AF XY:

0.00556

AC XY:

414

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.0215

AC:

893

AN:

41556

American (AMR)

AF:

0.000915

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000250

AC:

AN:

68038

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

141

188

235

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00232

Hom.:

Bravo

AF:

0.00660

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0159

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00188

AC:

228

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Dec 06, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 18550408, 20981092, 16996287) -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CPT2: BP4, BS1 -

Dec 17, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Carnitine palmitoyltransferase II deficiency

Benign:3

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Jan 06, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2022

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CPT2 c.302C>T (p.Ala101Val) results in a non-conservative amino acid change located in the Choline/carnitine acyltransferase domain (IPR039551) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 251458 control chromosomes, predominantly at a frequency of 0.021 within the African or African-American subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 13 fold of the estimated maximal expected allele frequency for a pathogenic variant in CPT2 causing Carnitine Palmitoyltransferase II Deficiency phenotype (0.0016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Carnitine palmitoyl transferase II deficiency, severe infantile form

Benign:2

Apr 11, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Carnitine palmitoyl transferase II deficiency, neonatal form

Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Carnitine palmitoyl transferase II deficiency, myopathic form

Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.53

D;.;.;T;T;T

Eigen

Benign

0.11

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.86

D;D;D;D;D;D

MetaRNN

Benign

0.0090

T;T;T;T;T;T

MetaSVM

Uncertain

-0.059

MutationAssessor

Pathogenic

3.0

M;.;.;.;.;.

PhyloP100

2.7

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.8

N;.;.;.;.;.

REVEL

Uncertain

0.45

Sift

Benign

0.16

T;.;.;.;.;.

Sift4G

Benign

0.16

T;.;.;.;.;.

Polyphen

0.30

B;.;.;.;.;.

Vest4

0.76

MVP

0.99

MPC

0.12

ClinPred

0.029

GERP RS

4.0

Varity_R

0.11

gMVP

0.33

Mutation Taster

=91/9

polymorphism

(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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rs75939866

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