rs17848485

Positions:

• chr1-53211308-A-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6 BS2_Supporting

The NM_000098.3(CPT2):​c.1634A>C​(p.Glu545Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000866 in 1,605,740 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts 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. E545K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00071 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00088 (4 hom.)
• Consequence: CPT2 NM_000098.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:3
• Conservation: PhyloP100: 9.32

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02558583).
• BP6: Variant 1-53211308-A-C is Benign according to our data. Variant chr1-53211308-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 166955.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=6}.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPT2	NM_000098.3	c.1634A>C	p.Glu545Ala	missense_variant	4/5	ENST00000371486.4	NP_000089.1
CPT2	NM_001330589.2	c.1576+58A>C		intron_variant			NP_001317518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPT2	ENST00000371486.4	c.1634A>C	p.Glu545Ala	missense_variant	4/5	1	NM_000098.3	ENSP00000360541.3

Frequencies

GnomAD3 genomes AF: 0.000710 AC: 108 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000803 AC: 187 AN: 232770 Hom.: 0 AF XY: 0.000786 AC XY: 99 AN XY: 125952

Gnomad AFR exome AF: 0.000481

Gnomad AMR exome AF: 0.000759

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000935

Gnomad SAS exome AF: 0.000488

Gnomad FIN exome AF: 0.00262

Gnomad NFE exome AF: 0.000665

Gnomad OTH exome AF: 0.000519

GnomAD4 exome AF: 0.000882 AC: 1282 AN: 1453420 Hom.: 4 Cov.: 34 AF XY: 0.000867 AC XY: 626 AN XY: 722326

Gnomad4 AFR exome AF: 0.000602

Gnomad4 AMR exome AF: 0.000757

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00314

Gnomad4 SAS exome AF: 0.000413

Gnomad4 FIN exome AF: 0.00237

Gnomad4 NFE exome AF: 0.000819

Gnomad4 OTH exome AF: 0.000549

GnomAD4 genome AF: 0.000709 AC: 108 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.000765 AC XY: 57 AN XY: 74484

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00273

Gnomad4 NFE AF: 0.000632

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000654 Hom.: 0

Bravo AF: 0.000521

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000684 AC: 3

ESP6500EA AF: 0.000701 AC: 6

ExAC AF: 0.000726 AC: 88

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 11, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 07, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 01, 2022	Reported as heterozygous in an asymptomatic infant with a positive newborn screen for CPT2 deficiency where another variant in CPT2 was not detected (Tajima et al., 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29429925, 26636822, 24503134, 20952238, 28074886, 28801073) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 14, 2023	PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	- -

Carnitine palmitoyltransferase II deficiency Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Sep 14, 2017

- -

CPT2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 28, 2022

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;.;T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T;T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.026	T;T;T
MetaSVM	Uncertain	0.50	D
MutationAssessor	Uncertain	2.1	M;.;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-5.3	D;.;.
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0020	D;.;.
Sift4G	Uncertain	0.0040	D;.;.
Polyphen		1.0	D;.;.
Vest4		0.80
MVP		1.0
MPC		0.57
ClinPred		0.085	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.83
gMVP		0.74

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: rs17848485; hg19: chr1-53676980;