rs74315299

Positions:

• chr1-53211034-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000098.3(CPT2):​c.1360G>T​(p.Glu454*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. E454E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CPT2 NM_000098.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.78

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-53211034-G-T is Pathogenic according to our data. Variant chr1-53211034-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 8966.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPT2	NM_000098.3	c.1360G>T	p.Glu454*	stop_gained	4/5	ENST00000371486.4	NP_000089.1
CPT2	NM_001330589.2	c.1360G>T	p.Glu454*	stop_gained	4/5		NP_001317518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPT2	ENST00000371486.4	c.1360G>T	p.Glu454*	stop_gained	4/5	1	NM_000098.3	ENSP00000360541.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Carnitine palmitoyl transferase II deficiency, myopathic form Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2005

- -

Carnitine palmitoyltransferase II deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 08, 2021

This sequence change creates a premature translational stop signal (p.Glu454*) in the CPT2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CPT2 are known to be pathogenic (PMID: 16781677, 16996287). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 8966). This premature translational stop signal has been observed in individual(s) with clinical features of carnitine palmitoyltransferase II deficiency (PMID: 15622536). This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.84
GERP RS		4.9

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: rs74315299; hg19: chr1-53676706;