rs142600166

chr1-53211193-G-Achr1-53211193-G-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1 PM2 BP4_Strong BP6

The NM_000098.3(CPT2):c.1519G>A(p.Val507Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000622 in 1,608,570 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V507G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: CPT2 NM_000098.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 0.0510

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 Likely_benign. Variant got -1 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000098.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.014255792).
• BP6: Variant 1-53211193-G-A is Benign according to our data. Variant chr1-53211193-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 429623.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2}. Variant chr1-53211193-G-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPT2	NM_000098.3	c.1519G>A	p.Val507Ile	missense_variant	4/5	ENST00000371486.4
CPT2	NM_001330589.2	c.1519G>A	p.Val507Ile	missense_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPT2	ENST00000371486.4	c.1519G>A	p.Val507Ile	missense_variant	4/5	1	NM_000098.3	P1
	ENST00000629810.1	n.286-784C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000207 AC: 51 AN: 246568 Hom.: 0 AF XY: 0.000150 AC XY: 20 AN XY: 133282

Gnomad AFR exome AF: 0.000997

Gnomad AMR exome AF: 0.0000584

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00148

Gnomad SAS exome AF: 0.0000335

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000359

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000446 AC: 65 AN: 1456302 Hom.: 0 Cov.: 34 AF XY: 0.0000470 AC XY: 34 AN XY: 723630

Gnomad4 AFR exome AF: 0.000689

Gnomad4 AMR exome AF: 0.0000449

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000531

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000722

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74454

Gnomad4 AFR AF: 0.000674

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.0000794 Hom.: 0

Bravo AF: 0.000261

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000222 AC: 27

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 20, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 06, 2018	The V507I variant has not been published as a pathogenicvariant, nor has it been reported as a benign variant to our knowledge. The V507I variant is observedin 12/8012 alleles (0.15%) alleles from individuals of East Asian background in large populationcohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The V507Ivariant is a conservative amino acid substitution, which is not likely to impact secondary proteinstructure as these residues share similar properties. This substitution occurs at a position that is notconserved. In silico analysis predicts this variant likely does not alter the protein structure/function. Insummary, based on the currently available information, it is unclear whether this variant is apathogenic variant or a rare benign variant. -

Carnitine palmitoyltransferase II deficiency Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 17, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	0.48
Dann	Benign	0.72
DEOGEN2	Benign	0.26	T;.;.;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.14	T;T;T;T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.014	T;T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.16	N;.;.;.;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.070	N;.;.;.;.
REVEL	Benign	0.24
Sift	Benign	1.0	T;.;.;.;.
Sift4G	Benign	0.64	T;.;.;.;.
Polyphen		0.0010	B;.;.;.;.
Vest4		0.063
MVP		0.75
MPC		0.092
ClinPred		0.0031	T
GERP RS		0.27
Varity_R		0.041
gMVP		0.099

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs142600166; hg19: chr1-53676865; COSMIC: COSV53758836; COSMIC: COSV53758836;