rs1553169975

Positions:

• chr1-53213384-CGAGCACACTGA-CT

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The ENST00000371486.4(CPT2):​c.1767_1777delinsT​(p.Ser590AlafsTer5) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. T589T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CPT2 ENST00000371486.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.91

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_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 12 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-53213385-GAGCACACTGA-T is Pathogenic according to our data. Variant chr1-53213385-GAGCACACTGA-T is described in ClinVar as [Pathogenic]. Clinvar id is 529858.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.1767_1777delinsT	p.Ser590AlafsTer5	frameshift_variant	5/5	ENST00000371486.4	NP_000089.1
CPT2	NM_001330589.2	c.1698_1708delinsT	p.Ser567AlafsTer5	frameshift_variant	5/5		NP_001317518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPT2	ENST00000371486.4	c.1767_1777delinsT	p.Ser590AlafsTer5	frameshift_variant	5/5	1	NM_000098.3	ENSP00000360541	P1
	ENST00000629810.1	n.78_88delinsA		non_coding_transcript_exon_variant	1/3	5

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Carnitine palmitoyltransferase II deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 21, 2020

This sequence change results in a premature translational stop signal in the CPT2 gene (p.Ser590Glufs*16). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 69 amino acids of the CPT2 protein. This variant is present in population databases (rs759017526, ExAC 0.009%). This variant has not been reported in the literature in individuals with CPT2-related disease. This variant disrupts the C-terminus of the CPT2 protein. Other variant(s) that disrupt this region (p.Glu645Argfs*5) have been determined to be pathogenic (PMID: 17936304, 21913903). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1553169975; hg19: chr1-53679057;