chr1-53211112-G-A

Position:

chr1-53211112-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_000098.3(CPT2):c.1438G>A(p.Gly480Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000626 in 1,614,056 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00067 ( 1 hom. )

Consequence

CPT2
NM_000098.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:12

Conservation

PhyloP100: 5.87

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 Likely_pathogenic. Variant got 6 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, 4 uncertain in NM_000098.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.896

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPT2	NM_000098.3 linkuse as main transcript	c.1438G>A	p.Gly480Arg	missense_variant	4/5	ENST00000371486.4
CPT2	NM_001330589.2 linkuse as main transcript	c.1438G>A	p.Gly480Arg	missense_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPT2	ENST00000371486.4 linkuse as main transcript	c.1438G>A	p.Gly480Arg	missense_variant	4/5	1	NM_000098.3	P1
	ENST00000629810.1 linkuse as main transcript	n.286-703C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000353

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000195

AC:

AN:

250908

Hom.:

AF XY:

0.000236

AC XY:

AN XY:

135676

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000423

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000672

AC:

982

AN:

1461738

Hom.:

Cov.:

AF XY:

0.000660

AC XY:

480

AN XY:

727154

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000861

Gnomad4 OTH exome

AF:

0.000331

GnomAD4 genome

AF:

0.000190

AC:

AN:

152318

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000353

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000565

Hom.:

Bravo

AF:

0.000295

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00104

AC:

ExAC

AF:

0.000148

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Carnitine palmitoyltransferase II deficiency

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 19, 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 31, 2022	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 480 of the CPT2 protein (p.Gly480Arg). This variant is present in population databases (rs201508063, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of CPT2-related conditions (PMID: 16996287). ClinVar contains an entry for this variant (Variation ID: 447218). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Carnitine palmitoyl transferase II deficiency, severe infantile form

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 14, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

Carnitine palmitoyl transferase II deficiency, neonatal form

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 25, 2022

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Aug 19, 2016

- -

Carnitine palmitoyl transferase II deficiency, myopathic form

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 26, 2023

The c.1438G>A (p.G480R) alteration is located in exon 4 (coding exon 4) of the CPT2 gene. This alteration results from a G to A substitution at nucleotide position 1438, causing the glycine (G) at amino acid position 480 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Apr 24, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

D;.;.;T;T

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

D;D;D;D;D

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.90

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.2

M;.;.;.;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-5.7

D;.;.;.;.

REVEL

Pathogenic

0.92

Sift

Uncertain

0.0040

D;.;.;.;.

Sift4G

Uncertain

0.0050

D;.;.;.;.

Polyphen

1.0

D;.;.;.;.

Vest4

0.62

MutPred

0.94

Gain of solvent accessibility (P = 0.0306);Gain of solvent accessibility (P = 0.0306);Gain of solvent accessibility (P = 0.0306);Gain of solvent accessibility (P = 0.0306);Gain of solvent accessibility (P = 0.0306);

MVP

0.99

MPC

0.60

ClinPred

0.84

GERP RS

5.8

Varity_R

0.78

gMVP

0.68

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