rs1799821

chr1-53210776-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000098.3(CPT2):c.1102G>A(p.Val368Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.516 in 1,613,682 control chromosomes in the GnomAD database, including 222,450 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V368V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.46 (17298 hom., cov: 32)
  • Exomes 𝑓: 0.52 (205152 hom.)
• Consequence: CPT2 NM_000098.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: -0.0480

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.4549217E-6).
• BP6: Variant 1-53210776-G-A is Benign according to our data. Variant chr1-53210776-G-A is described in ClinVar as [Benign]. Clinvar id is 92429.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-53210776-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.703 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPT2	NM_000098.3	c.1102G>A	p.Val368Ile	missense_variant	4/5	ENST00000371486.4
CPT2	NM_001330589.2	c.1102G>A	p.Val368Ile	missense_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPT2	ENST00000371486.4	c.1102G>A	p.Val368Ile	missense_variant	4/5	1	NM_000098.3	P1
	ENST00000629810.1	n.286-367C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.459 AC: 69707 AN: 151872 Hom.: 17289 Cov.: 32

Gnomad AFR AF: 0.289

Gnomad AMI AF: 0.685

Gnomad AMR AF: 0.449

Gnomad ASJ AF: 0.499

Gnomad EAS AF: 0.723

Gnomad SAS AF: 0.273

Gnomad FIN AF: 0.530

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.542

Gnomad OTH AF: 0.445

GnomAD3 exomes AF: 0.488 AC: 122480 AN: 251146 Hom.: 31996 AF XY: 0.482 AC XY: 65378 AN XY: 135760

Gnomad AFR exome AF: 0.282

Gnomad AMR exome AF: 0.438

Gnomad ASJ exome AF: 0.499

Gnomad EAS exome AF: 0.728

Gnomad SAS exome AF: 0.263

Gnomad FIN exome AF: 0.535

Gnomad NFE exome AF: 0.544

Gnomad OTH exome AF: 0.484

GnomAD4 exome AF: 0.522 AC: 762983 AN: 1461692 Hom.: 205152 Cov.: 60 AF XY: 0.515 AC XY: 374539 AN XY: 727142

Gnomad4 AFR exome AF: 0.284

Gnomad4 AMR exome AF: 0.432

Gnomad4 ASJ exome AF: 0.498

Gnomad4 EAS exome AF: 0.714

Gnomad4 SAS exome AF: 0.269

Gnomad4 FIN exome AF: 0.529

Gnomad4 NFE exome AF: 0.548

Gnomad4 OTH exome AF: 0.502

GnomAD4 genome AF: 0.459 AC: 69747 AN: 151990 Hom.: 17298 Cov.: 32 AF XY: 0.454 AC XY: 33736 AN XY: 74278

Gnomad4 AFR AF: 0.289

Gnomad4 AMR AF: 0.449

Gnomad4 ASJ AF: 0.499

Gnomad4 EAS AF: 0.722

Gnomad4 SAS AF: 0.272

Gnomad4 FIN AF: 0.530

Gnomad4 NFE AF: 0.542

Gnomad4 OTH AF: 0.451

Alfa AF: 0.522 Hom.: 53173

Bravo AF: 0.452

TwinsUK AF: 0.542 AC: 2009

ALSPAC AF: 0.549 AC: 2116

ESP6500AA AF: 0.290 AC: 1278

ESP6500EA AF: 0.542 AC: 4658

ExAC AF: 0.483 AC: 58689

Asia WGS AF: 0.438 AC: 1523 AN: 3478

EpiCase AF: 0.530

EpiControl AF: 0.527

ClinVar

Significance: Benign

Submissions summary: Benign:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 04, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 29, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Carnitine palmitoyltransferase II deficiency Benign:3 Other:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 07, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Carnitine palmitoyl transferase II deficiency, neonatal form Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

CPT2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 06, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Carnitine palmitoyl transferase II deficiency, severe infantile form Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	0.072
Dann	Benign	0.72
DEOGEN2	Benign	0.28	T;.;.;T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.70	T;T;T;T;T
MetaRNN	Benign	0.0000015	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.74	N;.;.;.;.
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.11	N;.;.;.;.
REVEL	Benign	0.23
Sift	Benign	1.0	T;.;.;.;.
Sift4G	Benign	1.0	T;.;.;.;.
Polyphen		0.011	B;.;.;.;.
Vest4		0.028
MPC		0.095
ClinPred		0.0050	T
GERP RS		-0.26
Varity_R		0.010
gMVP		0.11

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

Other links and lift over

dbSNP: rs1799821; hg19: chr1-53676448; COSMIC: COSV53758728; COSMIC: COSV53758728;