rs75939866

Positions:

chr1-53202391-C-T

Variant summary

Our verdict is Benign. Variant got -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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as 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 criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 2.65

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:

CPT2 (HGNC:):

CPT2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a topological_domain Mitochondrial matrix (size 152) in uniprot entity CPT2_HUMAN there are 20 pathogenic changes around while only 5 benign (80%) 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 [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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPT2	NM_000098.3 linkuse as main transcript	c.302C>T	p.Ala101Val	missense_variant	3/5	ENST00000371486.4	NP_000089.1	P23786A0A140VK13
CPT2	NM_001330589.2 linkuse as main transcript	c.302C>T	p.Ala101Val	missense_variant	3/5		NP_001317518.1	A0A1B0GTB8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPT2	ENST00000371486.4 linkuse as main transcript	c.302C>T	p.Ala101Val	missense_variant	3/5	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

GnomAD3 exomes

AF:

0.00155

AC:

389

AN:

251458

Hom.:

AF XY:

0.00118

AC XY:

160

AN XY:

135900

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 SAS 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

Gnomad4 AFR exome

AF:

0.0241

Gnomad4 AMR exome

AF:

0.000760

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000121

Gnomad4 OTH exome

AF:

0.00126

GnomAD4 genome

AF:

0.00611

AC:

930

AN:

152316

Hom.:

Cov.:

AF XY:

0.00556

AC XY:

414

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.0215

Gnomad4 AMR

AF:

0.000915

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00114

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

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 06, 2018	This variant is associated with the following publications: (PMID: 18550408, 20981092, 16996287) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 17, 2020	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Carnitine palmitoyltransferase II deficiency

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 03, 2022	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 06, 2017	- -

Carnitine palmitoyl transferase II deficiency, severe infantile form

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Carnitine palmitoyl transferase II deficiency, neonatal form

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Carnitine palmitoyl transferase II deficiency, myopathic form

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

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

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;.;.;.;.;.

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

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