rs1196469539

Positions:

chr1-53197042-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The ENST00000371486.4(CPT2):c.99G>C(p.Gln33His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000208 in 1,538,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

CPT2
ENST00000371486.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 0.806

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 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 ENST00000371486.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1517624).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPT2	NM_000098.3 linkuse as main transcript	c.99G>C	p.Gln33His	missense_variant	1/5	ENST00000371486.4	NP_000089.1
CPT2	NM_001330589.2 linkuse as main transcript	c.99G>C	p.Gln33His	missense_variant	1/5		NP_001317518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPT2	ENST00000371486.4 linkuse as main transcript	c.99G>C	p.Gln33His	missense_variant	1/5	1	NM_000098.3	ENSP00000360541	P1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000760

AC:

AN:

131544

Hom.:

AF XY:

0.0000139

AC XY:

AN XY:

71890

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000208

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000195

AC:

AN:

1386444

Hom.:

Cov.:

AF XY:

0.0000161

AC XY:

AN XY:

684328

show subpopulations

Gnomad4 AFR exome

AF:

0.0000318

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000223

Gnomad4 OTH exome

AF:

0.0000346

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152084

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74276

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Carnitine palmitoyl transferase II deficiency, severe infantile form

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 02, 2018	- -
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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Carnitine palmitoyltransferase II deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 18, 2022

This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 33 of the CPT2 protein (p.Gln33His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with CPT2-related conditions (PMID: 22494076). ClinVar contains an entry for this variant (Variation ID: 555897). 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 not 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.063

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.27

T;.;.;T;T;T

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.78

T;T;T;T;T;T

M_CAP

Benign

0.083

MetaRNN

Benign

0.15

T;T;T;T;T;T

MetaSVM

Benign

-0.79

MutationAssessor

Uncertain

2.1

M;.;.;.;.;.

MutationTaster

Benign

0.98

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.3

N;.;.;.;.;.

REVEL

Benign

0.15

Sift

Benign

0.083

T;.;.;.;.;.

Sift4G

Benign

0.095

T;.;.;.;.;.

Polyphen

0.012

B;.;.;.;.;.

Vest4

0.12

MutPred

0.20

Gain of glycosylation at S38 (P = 0.121);Gain of glycosylation at S38 (P = 0.121);Gain of glycosylation at S38 (P = 0.121);Gain of glycosylation at S38 (P = 0.121);Gain of glycosylation at S38 (P = 0.121);Gain of glycosylation at S38 (P = 0.121);

MVP

0.96

MPC

0.11

ClinPred

0.30

GERP RS

-1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.10

gMVP

0.38

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