rs147953465

chr1-53213424-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_000098.3(CPT2):c.1806T>C(p.Phe602=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00311 in 1,614,282 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0024 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0032 (17 hom.)
• Consequence: CPT2 NM_000098.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8
• Conservation: PhyloP100: 1.03

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 1-53213424-T-C is Benign according to our data. Variant chr1-53213424-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 460427.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=3, Likely_benign=2}. Variant chr1-53213424-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.03 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00319 (4657/1461890) while in subpopulation MID AF= 0.0199 (115/5768). AF 95% confidence interval is 0.017. There are 17 homozygotes in gnomad4_exome. There are 2284 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPT2	NM_000098.3	c.1806T>C	p.Phe602=	synonymous_variant	5/5	ENST00000371486.4
CPT2	NM_001330589.2	c.1737T>C	p.Phe579=	synonymous_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPT2	ENST00000371486.4	c.1806T>C	p.Phe602=	synonymous_variant	5/5	1	NM_000098.3	P1
	ENST00000629810.1	n.49A>G		non_coding_transcript_exon_variant	1/3	5

Frequencies

GnomAD3 genomes AF: 0.00241 AC: 367 AN: 152274 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00979

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00317

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00266 AC: 670 AN: 251492 Hom.: 3 AF XY: 0.00272 AC XY: 370 AN XY: 135920

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00332

Gnomad ASJ exome AF: 0.0132

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000523

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00324

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00319 AC: 4657 AN: 1461890 Hom.: 17 Cov.: 31 AF XY: 0.00314 AC XY: 2284 AN XY: 727246

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.00347

Gnomad4 ASJ exome AF: 0.0108

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000452

Gnomad4 FIN exome AF: 0.000168

Gnomad4 NFE exome AF: 0.00342

Gnomad4 OTH exome AF: 0.00376

GnomAD4 genome AF: 0.00241 AC: 367 AN: 152392 Hom.: 3 Cov.: 33 AF XY: 0.00229 AC XY: 171 AN XY: 74522

Gnomad4 AFR AF: 0.000625

Gnomad4 AMR AF: 0.00274

Gnomad4 ASJ AF: 0.00979

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00317

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00374 Hom.: 0

Bravo AF: 0.00280

Asia WGS AF: 0.000577 AC: 3 AN: 3478

EpiCase AF: 0.00333

EpiControl AF: 0.00373

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 28, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	CPT2: BP4, BP7, BS2 -

Carnitine palmitoyltransferase II deficiency Uncertain:1 Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 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. -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 28, 2020	- -

Carnitine palmitoyl transferase II deficiency, neonatal form Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

May 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
Cadd	Benign	14
Dann	Benign	0.80

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: rs147953465; hg19: chr1-53679096;